47 results on '"Soisson, Stephen M."'
Search Results
2. Stabilized trimeric peptide immunogens of the complete HIV-1 gp41 N-heptad repeat and their use as HIV-1 vaccine candidates.
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Chengwei Wu, Raheem, Izzat T., Nahas, Debbie D., Citron, Michael, Kim, Peter S., Montefiori, David C., Ottinger, Elizabeth A., Hepler, Robert W., Hrin, Renee, Patel, Sangita B., Soisson, Stephen M., and Joyce, Joseph G.
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PEPTIDES ,HIV ,IMMUNE response ,VACCINE development ,EPITOPES - Abstract
Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR-targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR-directed antibodies are potentiated in TZM-bl cells containing the FcγRI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV-1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and FcγR1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low-molecular-weight scaffolds that provide versatility in our immunogen presentation strategy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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3. From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9
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Petrilli, Whitney L., Adam, Gregory C., Erdmann, Roman S., Abeywickrema, Pravien, Agnani, Vijayalakshmi, Ai, Xi, Baysarowich, Jen, Byrne, Noel, Caldwell, John P., Chang, Wonsuk, DiNunzio, Edward, Feng, Zhe, Ford, Rachael, Ha, Sookhee, Huang, Yongcheng, Hubbard, Brian, Johnston, Jennifer M., Kavana, Michael, Lisnock, Jean-Marie, Liang, Rui, Lu, Jun, Lu, Zhijian, Meng, Juncai, Orth, Peter, Palyha, Oksana, Parthasarathy, Gopal, Salowe, Scott P., Sharma, Sujata, Shipman, Jennifer, Soisson, Stephen M., Strack, Alison M., Youm, Hyewon, Zhao, Kake, Zink, Deborah L., Zokian, Hratch, Addona, George H., Akinsanya, Karen, Tata, James R., Xiong, Yusheng, and Imbriglio, Jason E.
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- 2020
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4. Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation
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Hong, Chuan, Byrne, Noel J., Zamlynny, Beata, Tummala, Srivanya, Xiao, Li, Shipman, Jennifer M., Partridge, Andrea T., Minnick, Christina, Breslin, Michael J., Rudd, Michael T., Stachel, Shawn J., Rada, Vanessa L., Kern, Jeffrey C., Armacost, Kira A., Hollingsworth, Scott A., O’Brien, Julie A., Hall, Dawn L., McDonald, Terrence P., Strickland, Corey, Brooun, Alexei, Soisson, Stephen M., and Hollenstein, Kaspar
- Published
- 2021
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5. Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase
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Hayes, Robert P., Heo, Mee Ra, Mason, Mark, Reid, John, Burlein, Christine, Armacost, Kira A., Tellers, David M., Raheem, Izzat, Shaw, Anthony W., Murray, Edward, McKenna, Philip M., Abeywickrema, Pravien, Sharma, Sujata, Soisson, Stephen M., and Klein, Daniel
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- 2021
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6. Structural insights on ligand recognition at the human leukotriene B4 receptor 1
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Michaelian, Nairie, Sadybekov, Anastasiia, Besserer-Offroy, Élie, Han, Gye Won, Krishnamurthy, Harini, Zamlynny, Beata A., Fradera, Xavier, Siliphaivanh, Phieng, Presland, Jeremy, Spencer, Kerrie B., Soisson, Stephen M., Popov, Petr, Sarret, Philippe, Katritch, Vsevolod, and Cherezov, Vadim
- Published
- 2021
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7. Structural characterization of nonactive site, TrkA-selective kinase inhibitors
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Su, Hua-Poo, Rickert, Keith, Burlein, Christine, Narayan, Kartik, Bukhtiyarova, Marina, Hurzy, Danielle M., Stump, Craig A., Zhang, Xufang, Reid, John, Krasowska-Zoladek, Alicja, Tummala, Srivanya, Shipman, Jennifer M., Kornienko, Maria, Lemaire, Peter A., Krosky, Daniel, Heller, Amanda, Achab, Abdelghani, Chamberlin, Chad, Saradjian, Peter, Sauvagnat, Berengere, Yang, Xianshu, Ziebell, Michael R., Nickbarg, Elliott, Sanders, John M., Bilodeau, Mark T., Carroll, Steven S., Lumb, Kevin J., Soisson, Stephen M., Henze, Darrell A., and Cooke, Andrew J.
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- 2017
8. Structural Basis for Ligand-Regulated Oligomerization of AraC
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Soisson, Stephen M., MacDougall-Shackleton, Beth, Schleif, Robert, and Wolberger, Cynthia
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- 1997
9. A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein
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Tang, Aimin, Chen, Zhifeng, Cox, Kara S., Su, Hua-Poo, Callahan, Cheryl, Fridman, Arthur, Zhang, Lan, Patel, Sangita B., Cejas, Pedro J., Swoyer, Ryan, Touch, Sinoeun, Citron, Michael P., Govindarajan, Dhanasekaran, Luo, Bin, Eddins, Michael, Reid, John C., Soisson, Stephen M., Galli, Jennifer, Wang, Dai, Wen, Zhiyun, Heidecker, Gwendolyn J., Casimiro, Danilo R., DiStefano, Daniel J., and Vora, Kalpit A.
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- 2019
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10. Identification and structural and biophysical characterization of a positive modulator of human Kv3.1 channels.
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Yun-Ting Chen, Mee Ra Hong, Xin-Jun Zhang, Kostas, James, Yuxing Li, Kraus, Richard L., Santarelli, Vincent P., Wang, Deping, Gomez-Llorente, Yacob, Brooun, Alexei, Strickland, Corey, Soisson, Stephen M., Klein, Daniel J., Ginnetti, Anthony T., Marino, Michael J., Stachel, Shawn J., and Ishchenko, Andrii
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ACTION potentials ,ALZHEIMER'S disease ,DRUG design ,POTASSIUM channels ,MEMBRANE potential - Abstract
Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K
+ ) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders. [ABSTRACT FROM AUTHOR]- Published
- 2023
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11. Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis
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Ginnetti, Anthony T., Paone, Daniel V., Nanda, Kausik K., Li, Jing, Busuek, Marina, Johnson, Scott A., Lu, Jun, Soisson, Stephen M., Robinson, Ronald, Fisher, John, Webber, Andrea, Wesolowski, Gregg, Ma, Bennett, Duong, Le, Carroll, Steven, Burgey, Christopher S., and Stachel, Shawn J.
- Published
- 2022
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12. Identification of a Potent Synthetic FXR Agonist with an Unexpected Mode of Binding and Activation
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Soisson, Stephen M., Parthasarathy, Gopalakrishnan, Adams, Alan D., Sahoo, Soumya, Sitlani, Ayesha, Sparrow, Carl, Cui, Jisong, and Becker, Joseph W.
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- 2008
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13. Identification of potent inhibitors of the sortilin-progranulin interaction
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Stachel, Shawn J., Ginnetti, Anthony T., Johnson, Scott A., Cramer, Paige, Wang, Yi, Bukhtiyarova, Marina, Krosky, Daniel, Stump, Craig, Hurzy, Danielle M., Schlegel, Kelly-Ann, Cooke, Andrew J., Allen, Samantha, O'Donnell, Gregory, Ziebell, Michael, Parthasarathy, Gopal, Getty, Krista L., Ho, Thu, Ou, Yangsi, Jovanovska, Aneta, Carroll, Steve S., Pausch, Mark, Lumb, Kevin, Mosser, Scott D., Voleti, Bhavya, Klein, Daniel J., Soisson, Stephen M., Zerbinatti, Celina, and Coleman, Paul J.
- Published
- 2020
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14. Platensimycin is a selective FabF inhibitor with potent antibiotic properties
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Wang, Jun, Soisson, Stephen M., Young, Katherine, Shoop, Wesley, Kodali, Srinivas, Galgoci, Andrew, Painter, Ronald, Parthasarathy, Gopalakrishnan, Tang, Yui S., Cummings, Richard, Ha, Sookhee, Dorso, Karen, Motyl, Mary, Jayasuriya, Hiranthi, Ondeyka, John, Herath, Kithsiri, Zhang, Chaowei, Hernandez, Lorraine, Allocco, John, Basilio, Angela, Tormo, Jose R., Genilloud, Olga, Vicente, Francisca, Pelaez, Fernando, Colwell, Lawrence, Lee, Sang Ho, Michael, Bruce, Felcetto, Thomas, Gill, Charles, Silver, Lynn L., Hermes, Jeffery D., Bartizal, Ken, Barrett, John, Schmatz, Dennis, Becker, Joseph W., Cully, Doris, and Singh, Sheo B.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Jun Wang (corresponding author) [1, 3]; Stephen M. Soisson [1, 3]; Katherine Young [1]; Wesley Shoop [1, 2]; Srinivas Kodali [1]; Andrew Galgoci [1]; Ronald Painter [1]; Gopalakrishnan Parthasarathy [...]
- Published
- 2006
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15. Structural analysis of autoinhibition in the Ras activator Son of sevenless
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Sondermann, Holger, Soisson, Stephen M., Boykevisch, Sean, Yang, Shao-Song, Bar-Sagi, Dafna, and Kuriyan, John
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Cells -- Research ,Allosteric proteins -- Research ,Ras genes -- Research ,Biological sciences - Abstract
A crystallographic and biochemical analyses of a construct of Son of sevenless (SOS) that contains the Dbl homologypleckstrin homology (DH-PH) and catalytic domains is presented. It is observed that the DH-PH unit blocks the allosteric binding site for Ras and suppresses the activity of SOS.
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- 2004
16. Crystal structure of the Dbl and Pleckstrin homology domains from the Human Son of Sevenless protein
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Soisson, Stephen M., Nimnual, Anjaruwee S., Uy, Marc, Bar-Sagi, Dafna, and Kuriyan, John
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Proteins -- Research ,Rho(D) immune globulin -- Observations ,Biological sciences - Abstract
Proteins with Dbl homology (DH) domains operate as specific guanine nucleotide exchange factors, activating Rho-family GTPases. All DH domains have C-terminal pleckstrin homology (PH) domains that may be involved in targeting and regulatory functions. The crystal structure of a fragment of human Son of sevenless protein having the DH and PH domains, was determined at 2.3 A resolution. The active DH domain site is close to the interface between the DH and PH domains.
- Published
- 1998
17. From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9
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Petrilli, Whitney L., Adam, Gregory C., Erdmann, Roman S., Abeywickrema, Pravien, Agnani, Vijayalakshmi, Ai, Xi, Baysarowich, Jen, Byrne, Noel, Caldwell, John P., Chang, Wonsuk, DiNunzio, Edward, Feng, Zhe, Ford, Rachael, Ha, Sookhee, Huang, Yongcheng, Hubbard, Brian, Johnston, Jennifer M., Kavana, Michael, Lisnock, Jean-Marie, Liang, Rui, Lu, Jun, Lu, Zhijian, Meng, Juncai, Orth, Peter, Palyha, Oksana, Parthasarathy, Gopal, Salowe, Scott P., Sharma, Sujata, Shipman, Jennifer, Soisson, Stephen M., Strack, AlisonM., Youm, Hyewon, Zhao, Kake, Zink, Deborah L., Zokian, Hratch, Addona, George H., Akinsanya, Karen, Tata, James R., Xiong, Yusheng, and Imbriglio, Jason E.
- Published
- 2021
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18. The discovery and synthesis of potent zwitterionic inhibitors of renin
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Aspiotis, Renee, Chen, Austin, Cauchon, Elizabeth, Dubé, Daniel, Falgueyret, Jean-Pierre, Gagné, Sébastien, Gallant, Michel, Grimm, Erich L., Houle, Robert, Juteau, Hélène, Lacombe, Patrick, Laliberté, Sébastien, Lévesque, Jean-François, MacDonald, Dwight, McKay, Dan, Percival, M. David, Roy, Patrick, Soisson, Stephen M., and Wu, Tom
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- 2011
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19. Isolation, enzyme-bound structure and antibacterial activity of platencin A 1 from Streptomyces platensis
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Singh, Sheo B., Ondeyka, John G., Herath, Kithsiri B., Zhang, Chaowei, Jayasuriya, Hiranthi, Zink, Deborah L., Parthasarathy, Gopalakrishnan, Becker, Joseph W., Wang, Jun, and Soisson, Stephen M.
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- 2009
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20. Synthesis and biological evaluation of platensimycin analogs
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Shen, Hong C., Ding, Fa-Xiang, Singh, Sheo B., Parthasarathy, Gopalakrishnan, Soisson, Stephen M., Ha, Sookhee N., Chen, Xun, Kodali, Srinivas, Wang, Jun, Dorso, Karen, Tata, James R., Hammond, Milton L., MacCoss, Malcolm, and Colletti, Steven L.
- Published
- 2009
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21. Discoveryof 1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide(MK-8033): A Specific c-Met/Ron Dual Kinase Inhibitor withPreferential Affinity for the Activated State of c-Met.
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Northrup, Alan B., Katcher, Matthew H., Altman, Michael D., Chenard, Melissa, Daniels, Matthew H., Deshmukh, Sujal V., Falcone, Danielle, Guerin, David J., Hatch, Harold, Li, Chaomin, Lu, Wei, Lutterbach, Bart, Allison, Timothy J., Patel, Sangita B., Reilly, John F., Reutershan, Michael, Rickert, Keith W., Rosenstein, Craig, Soisson, Stephen M., and Szewczak, Alexander A.
- Published
- 2013
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22. Mechanism of Action of the Cell-Division Inhibitor PC190723: Modulation of FtsZ Assembly Cooperativity.
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Elsen, Nathaniel L., Lu, Jun, Parthasarathy, Gopal, Reid, John C., Sharma, Sujata, Soisson, Stephen M., and Lumb, Kevin J.
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- 2012
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23. Expression, purification and crystallization of human prolylcarboxypeptidase.
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Abeywickrema, Pravien D., Patel, Sangita B., Byrne, Noel J., Diehl, Ronald E., Hall, Dawn L., Ford, Rachael E., Rickert, Keith W., Reid, John C., Shipman, Jennifer M., Geissler, Wayne M., Pryor, Kelly D., SinhaRoy, Ranabir, Soisson, Stephen M., Lumb, Kevin J., and Sharma, Sujata
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CARBOXYPEPTIDASES ,PROTEIN expression ,PROTEIN fractionation ,CRYSTALLIZATION ,C-terminal residues ,LYSOSOMES ,GLYCOSYLATION ,SERINE - Abstract
Prolylcarboxypeptidase (PrCP) is a lysosomal serine carboxypeptidase that cleaves a variety of C-terminal amino acids adjacent to proline and has been implicated in diseases such as hypertension and obesity. Here, the robust production, purification and crystallization of glycosylated human PrCP from stably transformed CHO cells is described. Purified PrCP yielded crystals belonging to space group R32, with unit-cell parameters a = b = 181.14, c = 240.13 Å, that diffracted to better than 2.8 Å resolution. [ABSTRACT FROM AUTHOR]
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- 2010
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24. Structural definition and substrate specificity of theS28 protease family: the crystal structure of humanprolylcarboxypeptidase.
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Soisson, Stephen M., Patel, Sangita B., Abeywickrema, Pravien D., Byrne, Noel J., Diehl, Ronald E., Hall, Dawn L., Ford, Rachael E., Reid, John C., Rickert, Keith W., Shipman, Jennifer M., harma, Sujata, and Lumb, Kevin J.
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PROTEOLYTIC enzymes , *AMINOPEPTIDASES , *HYDROLASES , *PROLINE , *AMINO acids - Abstract
Background: The unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase DPP7. The structural basis of the different substrate specificities of the two enzymes is not understood nor has the structure of the S28 fold been described. Results: The experimentally phased 2.8 A crystal structure is presented for human PRCP. PRCP contains an α/β hydrolase domain harboring the catalytic Asp-His-Ser triad and a novel helical structural domain that caps the active site. Structural comparisons with prolylendopeptidase and DPP4 identify the S1 proline binding site of PRCP. A structure-based alignment with the previously undescribed structure of DPP7 illuminates the mechanism of orthogonal substrate specificity of PRCP and DPP7. PRCP has an extended active-site cleft that can accommodate proline substrates with multiple N-terminal residues. In contrast, the substrate binding groove of DPP7 is occluded by a short amino-acid insertion unique to DPP7 that creates a truncated active site selective for dipeptidyl proteolysis of Nterminal substrates. Conclusion: The results define the structure of the S28 family of proteases, provide the structural basis of PRCP and DPP7 substrate specificity and enable the rational design of selective PRCP modulators. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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25. Surface-entropy reduction approaches to manipulate crystal forms of β-ketoacyl acyl carrier protein synthase II from Streptococcus pneumoniae.
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Parthasarathy, Gopalakrishnan, Cummings, Richard, Becker, Joseph W., and Soisson, Stephen M.
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PROTEINS ,CRYSTALLIZATION ,CRYSTALLOGRAPHY ,CARRIER proteins ,CRYSTALLOIDS (Botany) - Abstract
A series of experiments with β-ketoacyl acyl carrier protein synthase II (FabF) from Streptococcus pneumonia (spFabF) were undertaken to evaluate the capability of surface-entropy reduction (SER) to manipulate protein crystallization. Previous work has shown that this protein crystallizes in two forms. The triclinic form contains four molecules in the asymmetric unit (a.u.) and diffracts to 2.1 Å resolution, while the more desirable primitive orthorhombic form contains one molecule in the a.u. and diffracts to 1.3 Å. The aim was to evaluate the effect of SER mutations that were specifically engineered to avoid perturbing the crystal-packing interfaces employed by the favorable primitive orthorhombic crystal form while potentially disrupting a surface of the protein employed by the less desirable triclinic crystal form. Two mutant proteins were engineered, each of which harbored five SER mutations. Extensive crystallization screening produced crystals of the two mutants, but only under conditions that differed from those used for the native protein. One of the mutant proteins yielded crystals that were of a new form (centered orthorhombic), despite the fact that the interfaces employed by the primitive orthorhombic form of the native protein were specifically unaltered. Structure determination at 1.75 Å resolution reveals that one of the mutations, E383A, appears to play a key role in disfavouring the less desirable triclinic crystal form and in generating a new surface for a packing interaction that stabilizes the new crystal form. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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26. Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
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Jun Wang, Soisson, Stephen M., Young, Katherine, Shoop, Wesley, Kodali, Srinivas, Galgoci, Andrew, Painter, Ronald, Parthasarathy, Gopalakrishnan, Tang, Yui S., Cummings, Richard, Sookhee Ha, Dorso, Karen, Motyl, Mary, Jayasuriya, Hiranthi, Ondeyka, John, Herath, Kithsiri, Chaowei Zhang, Hernandez, Lorraine, Allocco, John, and Basilio, Ángela
- Subjects
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BACTERIAL diseases , *ANTIBIOTICS , *DRUG resistance in microorganisms , *GRAM-negative bacteria , *BACTERIOLOGY , *PLATENSIMYCIN - Abstract
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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27. Tandem Histone Folds in the Structure of the N-Terminal Segment of the Ras Activator Son of Sevenless
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Sondermann, Holger, Soisson, Stephen M., Bar-Sagi, Dafna, and Kuriyan, John
- Subjects
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HISTONES , *NUCLEOTIDES , *CRYSTALS , *PROTEIN-protein interactions - Abstract
The Ras activator Son of Sevenless (Sos) contains a Cdc25 homology domain, responsible for nucleotide exchange, as well as Dbl/Pleckstrin homology (DH/PH) domains. We have determined the crystal structure of the N-terminal segment of human Sos1 (residues 1–191) and show that it contains two tandem histone folds. While the N-terminal domain is monomeric in solution, its structure is surprisingly similar to that of histone dimers, with both subunits of the histone “dimer” being part of the same peptide chain. One histone fold corresponds to the region of Sos that is clearly similar in sequence to histones (residues 91–191), whereas the other is formed by residues in Sos (1–90) that are unrelated in sequence to histones. Residues that form a contiguous patch on the surface of the histone domain of Sos are conserved from C. elegans to humans, suggesting a potential role for this domain in protein-protein interactions. [Copyright &y& Elsevier]
- Published
- 2003
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28. Clustering of Sp1 Sites Near the Promoter Region of ICP34.5 in Herpes Simplex Virus Type 1.
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Chung, In Kwon, Soisson, Stephen M., and Muller, Mark T.
- Published
- 1995
29. Identification of an allosteric binding site for RORγt inhibition.
- Author
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Scheepstra, Marcel, Leysen, Seppe, van Almen, Geert C., Miller, J. Richard, Piesvaux, Jennifer, Kutilek, Victoria, van Eenennaam, Hans, Zhang, Hongjun, Barr, Kenneth, Nagpal, Sunil, Soisson, Stephen M., Kornienko, Maria, Wiley, Kristen, Elsen, Nathaniel, Sharma, Sujata, Correll, Craig C., Trotter, B. Wesley, van der Stelt, Mario, Oubrie, Arthur, and Ottmann, Christian
- Published
- 2015
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30. ChemInform Abstract: Isolation, Enyzme-Bound Structure and Antibacterial Activity of Platencin A1 from Streptomyces platensis.
- Author
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Singh, Sheo B., Ondeyka, John G., Herath, Kithsiri B., Zhang, Chaowei, Jayasuriya, Hiranthi, Zink, Deborah L., Parthasarathy, Gopalakrishnan, Becker, Joseph W., Wang, Jun, and Soisson, Stephen M.
- Published
- 2009
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31. Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4.
- Author
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Allen, Samantha J., Parthasarathy, Gopal, Darke, Paul L., Diehl, Ronald E., Ford, Rachael E., Hall, Dawn L., Johnson, Scott A., Reid, John C., Rickert, Keith W., Shipman, Jennifer M., Soisson, Stephen M., Zuck, Paul, Munshi, Sanjeev K., and Lumb, Kevin J.
- Subjects
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G protein-coupled receptor kinases , *HYPERTENSION , *PHOSPHORYLATION , *REGULATION of blood pressure , *BIOCHEMICAL research - Abstract
G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V, and A486V) are associated with hypertension. Here, we describe the 2.6 Å structure of human GRK4α A486V crystallized in the presence of 5'-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4α is more similar to GRK2 than GRK6.Afully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the αB helix, αD helix, and the P-loop. Autophosphorylation of wildtype GRK4α is required for full kinase activity, as indicated by a lag in phosphorylation of a peptide from the dopamineD1 receptor without ATP preincubation. In contrast, this lag is not observed in GRK4α A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wildtype GRK4α, including Ser-485 in the kinase C-tail. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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32. Structure of the Bacterial Deacetylase LpxC Bound to the Nucleotide Reaction Product Reveals Mechanisms of Oxyanion Stabilization and Proton Transfer.
- Author
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Clayton, Gina M., Klein, Daniel J., Rickert, Keith W., Patel, Sangita B., Kornienko, Maria, Zugay-Murphy, Joan, Reid, John C., Tummala, Srivanya, Sharma, Sujata, Singh, Sheo B., Miesel, Lynn, Lumb, Kevin J., and Soisson, Stephen M.
- Subjects
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DEACETYLASES , *NUCLEOTIDES , *OXYANIONS , *OXYGEN compounds , *PROTON transfer reactions - Abstract
The emergence of antibiotic-resistant strains of pathogenic bacteria is an increasing threat to global health that underscores an urgent need for an expanded antibacterial armamentarium. Gram-negative bacteria, such as Escherichia coli, have become increasingly important clinical pathogens with limited treatment options. This is due in part to their lipopolysaccharide (LPS) outer membrane components, which dually serve as endotoxins while also protecting Gram-negative bacteria from antibiotic entry. The LpxC enzyme catalyzes the committed step of LPS biosynthesis, making LpxC a promising target for new antibacterials. Here, we present the first structure of an LpxC enzyme in complex with the deacetylation reaction product, UDP-(3-O-(R-3-hydroxymyristoyl))-glucosamine. These studies provide valuable insight into recognition of substrates and products by LpxC and a platform for structure-guided drug discovery broad spectrum Gram-negative antibiotics. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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33. Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met.
- Author
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Rickert, Keith W., Patel, Sangita B., Allison, Timothy J., Byrne, Noel J., Darke, Paul L., Ford, Rachael E., Guerin, David J., Hall, Dawn L., Kornienko, Maria, Jun Lu, Munshi, Sanjeev K., Reid, John C., Shipman, Jennifer M., Stanton, Elizabeth F., Wilson, Kevin J., Young, Jonathon R., Soisson, Stephen M., and Lumb, Kevin J.
- Subjects
- *
HEPATOCYTE growth factor , *PROTEIN-tyrosine kinases , *CARCINOGENESIS , *CANCER treatment , *CELL receptors , *PHOSPHORYLATION , *LIGAND binding (Biochemistry) , *MATERIAL plasticity - Abstract
The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix aC and the G loop to generate a viable active site. Helix aC adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c-Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
34. Development of a robust crystallization platform for immune receptor TREM2 using a crystallization chaperone strategy.
- Author
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Byrne, Noel J., Lee, Amy C., Kostas, James, Reid, John C., Partridge, Andrea T., So, Sung-Sau, Cowan, Joseph E., Abeywickrema, Pravien, Huang, Hua, Zebisch, Matthias, Barker, John J., Soisson, Stephen M., Brooun, Alexei, and Su, Hua-Poo
- Subjects
- *
CRYSTALLIZATION , *GENOMICS , *SMALL molecules , *CRYSTALLOIDS (Botany) , *ALZHEIMER'S disease - Abstract
TREM2 has been identified by genomic analysis as a potential and novel target for the treatment of Alzheimer's disease. To enable structure-based screening of potential small molecule therapeutics, we sought to develop a robust crystallization platform for the TREM2 Ig-like domain. A systematic set of constructs containing the structural chaperone, maltose binding protein (MBP), fused to the Ig domain of TREM2, were evaluated in parallel expression and purification, followed by crystallization studies. Using protein crystallization and high-resolution diffraction as a readout, a MBP-TREM2 Ig fusion construct was identified that generates reproducible protein crystals diffracting at 2.0 Å, which makes it suitable for soaking of potential ligands. Importantly, analysis of crystal packing interfaces indicates that most of the surface of the TREM2 Ig domain is available for small molecule binding. A proof of concept co-crystallization study with a small library of fragments validated potential utility of this system for the discovery of new TREM2 therapeutics. • TREM2 genetic variants are associated with Alzheimer disease and Nasu-Hakola disease. • Molecules that modulate TREM2 signaling may lead to therapies for Alzheimer disease. • TREM2 crystallization system developed using an MBP fusion as structural chaperone. • Robust crystallization system could support small molecule screening campaigns. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
35. Stabilized trimeric peptide immunogens of the complete HIV-1 gp41 N-heptad repeat and their use as HIV-1 vaccine candidates.
- Author
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Wu C, Raheem IT, Nahas DD, Citron M, Kim PS, Montefiori DC, Ottinger EA, Hepler RW, Hrin R, Patel SB, Soisson SM, and Joyce JG
- Subjects
- Animals, Humans, Mice, Epitopes immunology, HIV Infections immunology, HIV Infections prevention & control, HIV Infections virology, Peptides immunology, Peptides chemistry, Female, Antibodies, Monoclonal immunology, HIV Envelope Protein gp41 immunology, HIV Envelope Protein gp41 chemistry, HIV-1 immunology, AIDS Vaccines immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology
- Abstract
Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR-targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR-directed antibodies are potentiated in TZM-bl cells containing the FcγRI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV-1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and FcγR1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low-molecular-weight scaffolds that provide versatility in our immunogen presentation strategy., Competing Interests: Competing interests statement:C.W., I.T.R., P.S.K., D.D.N., M.C., E.A.O., R.W.H., S.B.P., R.H., S.M.S., and J.G.J. were employees of Merck & Co., Inc. at the time when the work was performed, and may own Merck stock exceeding $5,000. The authors disclose a patent application relevant to this study: World Intellectual Property Organization, WO2013142298 A1 2013-09-26.
- Published
- 2024
- Full Text
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36. Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.
- Author
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Chen YT, Hong MR, Zhang XJ, Kostas J, Li Y, Kraus RL, Santarelli VP, Wang D, Gomez-Llorente Y, Brooun A, Strickland C, Soisson SM, Klein DJ, Ginnetti AT, Marino MJ, Stachel SJ, and Ishchenko A
- Subjects
- Humans, Potassium Channels metabolism, Action Potentials physiology, Membrane Proteins metabolism, Neurons metabolism, Potassium Channels, Voltage-Gated metabolism
- Abstract
Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K
+ ) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.- Published
- 2023
- Full Text
- View/download PDF
37. A non-canonical mechanism of GPCR activation.
- Author
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Powers AS, Khan A, Paggi JM, Latorraca NR, Souza S, Salvo JD, Lu J, Soisson SM, Johnston JM, Weinglass AB, and Dror RO
- Abstract
The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists-ligands that trigger GPCR activation-function by causing rearrangement of the GPCR's transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations which disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets., Competing Interests: Competing Financial Interests A.K., S.S., J.D.S., J.L., S.M.S., J.M.J., A.M.W. are current or past employees of Merck Research Laboratories.
- Published
- 2023
- Full Text
- View/download PDF
38. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.
- Author
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Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, and Soisson SM
- Subjects
- Allosteric Regulation, Binding Sites, Crystallography, X-Ray, Humans, Models, Molecular, Protein Binding, Protein Conformation, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled chemistry
- Abstract
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
- Published
- 2017
- Full Text
- View/download PDF
39. Insights into activity and inhibition from the crystal structure of human O-GlcNAcase.
- Author
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Elsen NL, Patel SB, Ford RE, Hall DL, Hess F, Kandula H, Kornienko M, Reid J, Selnick H, Shipman JM, Sharma S, Lumb KJ, Soisson SM, and Klein DJ
- Subjects
- Acetylglucosamine metabolism, Binding Sites, Calorimetry, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Humans, Protein Structure, Tertiary, Substrate Specificity, Models, Biological, beta-N-Acetylhexosaminidases chemistry, beta-N-Acetylhexosaminidases metabolism
- Abstract
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities.
- Published
- 2017
- Full Text
- View/download PDF
40. Structural basis for selectivity and diversity in angiotensin II receptors.
- Author
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Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N, Sadybekov A, Zamlynny B, Rudd MT, Hollenstein K, Tolstikova A, White TA, Hunter MS, Weierstall U, Liu W, Babaoglu K, Moore EL, Katz RD, Shipman JM, Garcia-Calvo M, Sharma S, Sheth P, Soisson SM, Stevens RC, Katritch V, and Cherezov V
- Subjects
- Angiotensin II Type 2 Receptor Blockers chemistry, Angiotensin II Type 2 Receptor Blockers metabolism, Binding Sites genetics, Crystallography, X-Ray, Drug Design, Heterotrimeric GTP-Binding Proteins chemistry, Heterotrimeric GTP-Binding Proteins metabolism, Humans, Ligands, Molecular Docking Simulation, Mutation, Protein Binding, Protein Conformation, Receptor, Angiotensin, Type 1 chemistry, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 agonists, Receptor, Angiotensin, Type 2 genetics, Signal Transduction, Structure-Activity Relationship, Substrate Specificity genetics, beta-Arrestins metabolism, Models, Molecular, Receptor, Angiotensin, Type 2 chemistry, Receptor, Angiotensin, Type 2 metabolism
- Abstract
The angiotensin II receptors AT
1 R and AT2 R serve as key components of the renin-angiotensin-aldosterone system. AT1 R has a central role in the regulation of blood pressure, but the function of AT2 R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT2 R bound to an AT2 R-selective ligand and to an AT1 R/AT2 R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.- Published
- 2017
- Full Text
- View/download PDF
41. Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode.
- Author
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Lu J, Patel S, Sharma N, Soisson SM, Kishii R, Takei M, Fukuda Y, Lumb KJ, and Singh SB
- Subjects
- Aminoglycosides metabolism, Binding Sites, Crystallography, X-Ray, DNA Gyrase metabolism, DNA Topoisomerase IV metabolism, Models, Molecular, Molecular Structure, Naphthalenes metabolism, Novobiocin metabolism, Protein Conformation, Protein Multimerization, Pyrroles chemistry, Pyrroles metabolism, Pyrrolidinones chemistry, Pyrrolidinones metabolism, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors metabolism, Topoisomerase Inhibitors chemistry, Topoisomerase Inhibitors metabolism, Aminoglycosides chemistry, DNA Gyrase chemistry, DNA Topoisomerase IV chemistry, Naphthalenes chemistry, Novobiocin chemistry, Staphylococcus aureus chemistry
- Abstract
Bacterial resistance to antibiotics continues to pose serious challenges as the discovery rate for new antibiotics fades. Kibdelomycin is one of the rare, novel, natural product antibiotics discovered recently that inhibits the bacterial DNA synthesis enzymes gyrase and topoisomerase IV. It is a broad-spectrum, Gram-positive antibiotic without cross-resistance to known gyrase inhibitors, including clinically effective quinolones. To understand its mechanism of action, binding mode, and lack of cross-resistance, we have co-crystallized kibdelomycin and novobiocin with the N-terminal domains of Staphylococcus aureus gyrase B (24 kDa) and topo IV (ParE, 24 and 43 kDa). Kibdelomycin shows a unique "dual-arm", U-shaped binding mode in both crystal structures. The pyrrolamide moiety in the lower part of kibdelomycin penetrates deeply into the ATP-binding site pocket, whereas the isopropyl-tetramic acid and sugar moiety of the upper part thoroughly engage in polar interactions with a surface patch of the protein. The isoproramic acid (1,3-dioxopyrrolidine) and a tetrahydropyran acetate group (Sugar A) make polar contact with a surface area consisting of helix α4 and the flexible loop connecting helices α3 and α4. The two arms are connected together by a rigid decalin linker that makes van del Waals contacts with the protein backbone. This "dual-arm", U-shaped, multicontact binding mode of kibdelomycin is unique and distinctively different from binding modes of other known gyrase inhibitors (e.g., coumarins and quinolones), which explains its lack of cross-resistance and low frequency of resistance. The crystal structures reported in this paper should enable design and discovery of analogues with better properties and antibacterial spectrum.
- Published
- 2014
- Full Text
- View/download PDF
42. Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.
- Author
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Northrup AB, Katcher MH, Altman MD, Chenard M, Daniels MH, Deshmukh SV, Falcone D, Guerin DJ, Hatch H, Li C, Lu W, Lutterbach B, Allison TJ, Patel SB, Reilly JF, Reutershan M, Rickert KW, Rosenstein C, Soisson SM, Szewczak AA, Walker D, Wilson K, Young JR, Pan BS, and Dinsmore CJ
- Subjects
- Animals, Benzocycloheptenes chemistry, Cell Line, Tumor, Dogs, Enzyme Activation drug effects, Female, Humans, Mice, Models, Molecular, Protein Conformation, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met chemistry, Rats, Substrate Specificity, Sulfonamides chemistry, Xenograft Model Antitumor Assays, Benzocycloheptenes metabolism, Benzocycloheptenes pharmacology, Drug Discovery, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met metabolism, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Sulfonamides metabolism, Sulfonamides pharmacology
- Abstract
This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.
- Published
- 2013
- Full Text
- View/download PDF
43. Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics.
- Author
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Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM, Elsen NL, Wu J, Deschamps K, Petcu M, Wong S, Daigneault E, Kramer S, Liang L, Maxwell E, Claveau D, Vaillancourt J, Skorey K, Tam J, Wang H, Meredith TC, Sillaots S, Wang-Jarantow L, Ramtohul Y, Langlois E, Landry F, Reid JC, Parthasarathy G, Sharma S, Baryshnikova A, Lumb KJ, Pinho MG, Soisson SM, and Roemer T
- Subjects
- Animals, Anti-Bacterial Agents therapeutic use, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Cell Division drug effects, Crystallography, X-Ray, Cytoskeletal Proteins antagonists & inhibitors, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins metabolism, Disease Models, Animal, Drug Resistance, Bacterial drug effects, Drug Synergism, Gene Regulatory Networks genetics, Guanosine Diphosphate, Imipenem pharmacology, Methicillin-Resistant Staphylococcus aureus cytology, Methicillin-Resistant Staphylococcus aureus pathogenicity, Mice, Microbial Sensitivity Tests, Mutation genetics, Protein Structure, Secondary, Protein Transport drug effects, Pyridines chemistry, Pyridines pharmacology, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Thiazoles chemistry, Thiazoles pharmacology, Virulence drug effects, beta-Lactams therapeutic use, Anti-Bacterial Agents pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, beta-Lactams pharmacology
- Abstract
Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with β-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the β-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to β-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.
- Published
- 2012
- Full Text
- View/download PDF
44. Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer.
- Author
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Katz JD, Jewell JP, Guerin DJ, Lim J, Dinsmore CJ, Deshmukh SV, Pan BS, Marshall CG, Lu W, Altman MD, Dahlberg WK, Davis L, Falcone D, Gabarda AE, Hang G, Hatch H, Holmes R, Kunii K, Lumb KJ, Lutterbach B, Mathvink R, Nazef N, Patel SB, Qu X, Reilly JF, Rickert KW, Rosenstein C, Soisson SM, Spencer KB, Szewczak AA, Walker D, Wang W, Young J, and Zeng Q
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Benzocycloheptenes pharmacokinetics, Benzocycloheptenes pharmacology, Cell Line, Tumor, Crystallography, X-Ray, Dogs, Drug Screening Assays, Antitumor, Female, Haplorhini, Humans, Mice, Mice, Nude, Models, Molecular, Mutation, Neoplasm Transplantation, Phosphorylation, Protein Binding, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Receptor Protein-Tyrosine Kinases genetics, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Benzocycloheptenes chemical synthesis, Pyridines chemical synthesis, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.
- Published
- 2011
- Full Text
- View/download PDF
45. Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.
- Author
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Shen HC, Ding FX, Wang S, Deng Q, Zhang X, Chen Y, Zhou G, Xu S, Chen HS, Tong X, Tong V, Mitra K, Kumar S, Tsai C, Stevenson AS, Pai LY, Alonso-Galicia M, Chen X, Soisson SM, Roy S, Zhang B, Tata JR, Berger JP, and Colletti SL
- Subjects
- Animals, Biological Availability, Cell Line, Crystallography, X-Ray, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System metabolism, Eicosanoids metabolism, Epoxy Compounds metabolism, Humans, In Vitro Techniques, Ion Channels antagonists & inhibitors, Ion Channels metabolism, Kidney drug effects, Kidney metabolism, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Models, Molecular, Molecular Conformation, Muscle Relaxation, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Piperidines pharmacokinetics, Piperidines pharmacology, Rats, Rats, Inbred SHR, Solubility, Stereoisomerism, Structure-Activity Relationship, Urea pharmacokinetics, Urea pharmacology, Epoxide Hydrolases antagonists & inhibitors, Piperidines chemical synthesis, Urea analogs & derivatives, Urea chemical synthesis
- Abstract
4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
- Published
- 2009
- Full Text
- View/download PDF
46. Surface-entropy reduction approaches to manipulate crystal forms of beta-ketoacyl acyl carrier protein synthase II from Streptococcus pneumoniae.
- Author
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Parthasarathy G, Cummings R, Becker JW, and Soisson SM
- Subjects
- 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase genetics, Amino Acid Substitution, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Crystallography, X-Ray methods, Entropy, Models, Molecular, Mutagenesis, Site-Directed, Protein Structure, Secondary, 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase chemistry, 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase metabolism, Streptococcus pneumoniae enzymology
- Abstract
A series of experiments with beta-ketoacyl acyl carrier protein synthase II (FabF) from Streptococcus pneumonia (spFabF) were undertaken to evaluate the capability of surface-entropy reduction (SER) to manipulate protein crystallization. Previous work has shown that this protein crystallizes in two forms. The triclinic form contains four molecules in the asymmetric unit (a.u.) and diffracts to 2.1 A resolution, while the more desirable primitive orthorhombic form contains one molecule in the a.u. and diffracts to 1.3 A. The aim was to evaluate the effect of SER mutations that were specifically engineered to avoid perturbing the crystal-packing interfaces employed by the favorable primitive orthorhombic crystal form while potentially disrupting a surface of the protein employed by the less desirable triclinic crystal form. Two mutant proteins were engineered, each of which harbored five SER mutations. Extensive crystallization screening produced crystals of the two mutants, but only under conditions that differed from those used for the native protein. One of the mutant proteins yielded crystals that were of a new form (centered orthorhombic), despite the fact that the interfaces employed by the primitive orthorhombic form of the native protein were specifically unaltered. Structure determination at 1.75 A resolution reveals that one of the mutations, E383A, appears to play a key role in disfavouring the less desirable triclinic crystal form and in generating a new surface for a packing interaction that stabilizes the new crystal form.
- Published
- 2008
- Full Text
- View/download PDF
47. Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis.
- Author
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Becker JW, Rotonda J, Soisson SM, Aspiotis R, Bayly C, Francoeur S, Gallant M, Garcia-Calvo M, Giroux A, Grimm E, Han Y, McKay D, Nicholson DW, Peterson E, Renaud J, Roy S, Thornberry N, and Zamboni R
- Subjects
- Caspase 3, Caspase Inhibitors, Crystallography, X-Ray, Heterocyclic Compounds, 3-Ring chemistry, Ligands, Models, Molecular, Molecular Mimicry, Molecular Structure, Niacin analogs & derivatives, Niacin chemistry, Oligopeptides chemistry, Protein Conformation, Pyrazines chemistry, Structure-Activity Relationship, Caspases chemistry, Enzyme Inhibitors chemistry, Peptides chemistry
- Abstract
Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.
- Published
- 2004
- Full Text
- View/download PDF
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