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334 results on '"Myler, Peter J."'

1. Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens

Author

Fenwick, Michael K., Pierce, Phillip G., Abendroth, Jan, Barrett, Kayleigh F., Barrett, Lynn K., Bowatte, Kalinga, Choi, Ryan, Chun, Ian, Conrady, Deborah G., Craig, Justin K., Dranow, David M., Hammerson, Bradley, Higgins, Tate, Lorimer, Donald D., Lukat, Peer, Mayclin, Stephen J., Hewitt, Stephen Nakazawa, Peng, Ying Po, Shanbhogue, Ashwini, Smutney, Hayden, Stigliano, Matthew Z. Z., Tillery, Logan M., Udell, Hannah S., Wallace, Ellen G., DeRocher, Amy E., Phan, Isabelle Q., Staker, Bart L., Subramanian, Sandhya, Van Voorhis, Wesley C., Blankenfeldt, Wulf, Müller, Rolf, Edwards, Thomas E., and Myler, Peter J.

Published
2024
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6. Co‐crystal structure of Helicobacter pylori biotin protein ligase with biotinyl‐5‐ATP.

Author

Ayanlade, Jesuferanmi P., Davis, Dylan E., Subramanian, Sandhya, Dranow, David M., Lorimer, Donald D., Hammerson, Brad, Myler, Peter J., and Asojo, Oluwatoyin A.

Subjects
HELICOBACTER pylori, STOMACH ulcers, BACTERIAL proteins, BANKING industry, MYCOBACTERIUM tuberculosis, GASTRIC mucosa
Abstract

Helicobacter pylori, a type 1 carcinogen that causes human gastric ulcers and cancer, is a priority target of the Seattle Structural Genomics Center for Infectious Disease (SSGCID). These efforts include determining the structures of potential H. pylori therapeutic targets. Here, the purification, crystallization and X‐ray structure of one such target, H. pylori biotin protein ligase (HpBPL), are reported. HpBPL catalyzes the activation of various biotin‐dependent metabolic pathways, including fatty‐acid synthesis, gluconeogenesis and amino‐acid catabolism, and may facilitate the survival of H. pylori in the high‐pH gastric mucosa. HpBPL is a prototypical bacterial biotin protein ligase, despite having less than 35% sequence identity to any reported structure in the Protein Data Bank. A biotinyl‐5‐ATP molecule sits in a well conserved cavity. HpBPL shares extensive tertiary‐structural similarity with Mycobacterium tuberculosis biotin protein ligase (MtBPL), despite having less than 22% sequence identity. The active site of HpBPL is very similar to that of MtBPL and has the necessary residues to bind inhibitors developed for MtBPL. [ABSTRACT FROM AUTHOR]

Published
2025
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7. Structure of Plasmodium vivaxN‐myristoyltransferase with inhibitor IMP‐1088: exploring an NMT inhibitor for antimalarial therapy.

Author

Mendez, Alex, Bolling, Cydni, Taylor, Shane, Makumire, Stanley, Staker, Bart, Reers, Alexandra, Hammerson, Brad, Mayclin, Stephen J., Abendroth, Jan, Lorimer, Donald D., Edwards, Thomas E., Tate, Edward W., Subramanian, Sandhya, Bell, Andrew S., Myler, Peter J., Asojo, Oluwatoyin A., and Chakafana, Graham

Subjects
DRUG repositioning, COMMUNICABLE diseases, MALARIA, CLIMATE change, PLASMODIUM, PLASMODIUM vivax
Abstract

Plasmodium vivax, a significant contributor to global malaria cases, poses an escalating health burden on a substantial portion of the world's population. The increasing spread of P. vivax because of climate change underscores the development of new and rational drug‐discovery approaches. The Seattle Structural Genomics Center for Infectious Diseases is taking a structure‐based approach by investigating essential enzymes such as N‐myristoyltransferase (NMT). P. vivaxN‐myristoyltransferase (PvNMT) is a promising target for the development of novel malaria treatments unlike current drugs, which target only the erythrocytic stages of the parasite. Here, the 1.8 Å resolution ternary structure of PvNMT in complex with myristoyl‐CoA and IMP‐1088, a validated NMT inhibitor, is reported. IMP‐1088 is a validated nonpeptidic inhibitor and a ternary complex structure with human NMT has previously been reported. IMP‐1088 binds similarly to PvNMT as to human NMT. [ABSTRACT FROM AUTHOR]

Published
2025
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8. Structures of Trichomonas vaginalis macrophage migratory inhibitory factor.

Author

Srivastava, Aruesha, Nair, Aryana, Dawson, Omolara C. O., Gao, Raymond, Liu, Lijun, Craig, Justin K., Battaile, Kevin P., Harmon, Elizabeth K., Barrett, Lynn K., Van Voorhis, Wesley C., Subramanian, Sandhya, Myler, Peter J., Lovell, Scott, Asojo, Oluwatoyin A., and Darwiche, Rabih

Subjects
MACROPHAGE migration inhibitory factor, SEXUALLY transmitted diseases, TRICHOMONAS vaginalis, DRUG discovery, COMMUNICABLE diseases
Abstract

The unicellular parasitic protozoan Trichomonas vaginalis causes trichomoniasis, the most prevalent nonviral sexually transmitted disease globally. T. vaginalis evades host immune responses by producing homologs of host proteins, including cytokines such as macrophage migration inhibitory factor. T. vaginalis macrophage migration inhibitory factor (TvMIF) helps to facilitate the survival of T. vaginalis during nutritional stress conditions, increases prostate cell proliferation and invasiveness, and induces inflammation‐related cellular pathways, thus mimicking the ability of human MIF to increase inflammation and cell proliferation. The production, crystallization and three structures of N‐terminally hexahistidine‐tagged TvMIF reveal a prototypical MIF trimer with a topology similar to that of human homologs (hMIF‐1 and hMIF‐2). The N‐terminal tag obscures the expected pyruvate‐binding site. The similarity of TvMIF to its human homologs can be exploited for structure‐based drug discovery. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Crystal structure of glutamyl‐tRNA synthetase from Helicobacter pylori.

Author

Davis, Dylan E., Ayanlade, Jesuferanmi P., Laseinde, David T., Subramanian, Sandhya, Udell, Hannah, Lorimer, Donald J., Dranow, David M., Edwards, Thomas E., Myler, Peter J., and Asojo, Oluwatoyin A.

Subjects
TRANSMISSIBLE tumors, DRUG discovery, STOMACH ulcers, BACTERIAL diseases, COMMUNICABLE diseases, HELICOBACTER pylori, TRANSFER RNA
Abstract

Helicobacter pylori is one of the most common bacterial infections; over two‐thirds of the world's population is infected by early childhood. Persistent H. pylori infection results in gastric ulcers and cancers. Due to drug resistance, there is a need to develop alternative treatments to clear H. pylori. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducts structure–function analysis of potential therapeutic targets from H. pylori. Glutamyl‐tRNA synthetase (GluRS) is essential for tRNA aminoacylation and is under investigation as a bacterial drug target. The SSGCID produced, crystallized and determined the apo structure of H. pylori GluRS (HpGluRS). HpGluRS has the prototypical bacterial GluRS topology and has similar binding sites and tertiary structures to other bacterial GluRS that are promising drug targets. Residues involved in glutamate binding are well conserved in comparison with Pseudomonas aeruginosa GluRS (PaGluRS), which has been studied to develop promising new inhibitors for P. aeruginosa. These structural similarities can be exploited for drug discovery and repurposing to generate new antibacterials to clear persistent H. pylori infection and reduce gastric ulcers and cancer. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Ternary structure of Plasmodium vivaxN‐myristoyltransferase with myristoyl‐CoA and inhibitor IMP‐0001173.

Author

Bolling, Cydni, Mendez, Alex, Taylor, Shane, Makumire, Stanley, Reers, Alexandra, Zigweid, Rachael, Subramanian, Sandhya, Dranow, David M., Staker, Bart, Edwards, Thomas E., Tate, Edward W., Bell, Andrew S., Myler, Peter J., Asojo, Oluwatoyin A., and Chakafana, Graham

Subjects
GLUCOSE-6-phosphate dehydrogenase deficiency, PLASMODIUM vivax, HEMOLYTIC anemia, MALARIA, COMMUNICABLE diseases, GLUCOSE-6-phosphate dehydrogenase
Abstract

Plasmodium vivax is a major cause of malaria, which poses an increased health burden on approximately one third of the world's population due to climate change. Primaquine, the preferred treatment for P. vivax malaria, is contraindicated in individuals with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, a common genetic cause of hemolytic anemia, that affects ∼2.5% of the world's population and ∼8% of the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducted a structure–function analysis of P. vivaxN‐myristoyltransferase (PvNMT) as part of efforts to develop alternative malaria drugs. PvNMT catalyzes the attachment of myristate to the N‐terminal glycine of many proteins, and this critical post‐translational modification is required for the survival of P. vivax. The first step is the formation of a PvNMT–myristoyl–CoA binary complex that can bind to peptides. Understanding how inhibitors prevent protein binding will facilitate the development of PvNMT as a viable drug target. NMTs are secreted in all life stages of malarial parasites, making them attractive targets, unlike current antimalarials that are only effective during the plasmodial erythrocytic stages. The 2.3 Å resolution crystal structure of the ternary complex of PvNMT with myristoyl‐CoA and a novel inhibitor is reported. One asymmetric unit contains two monomers. The structure reveals notable differences between the PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Structures of Brucella ovis leucine‐, isoleucine‐, valine‐, threonine‐ and alanine‐binding protein reveal a conformationally flexible peptide‐binding cavity.

Author

Chakafana, Graham, Boswell, Reghan, Chandler, Andrew, Jackson, Krishelle A., Neblett, Sanai, Postal, Tyler, Subramanian, Sandhya, Abendroth, Jan, Myler, Peter J., and Asojo, Oluwatoyin A.

Subjects
SCIENTIFIC communication, CARRIER proteins, SMALL molecules, DRUG repositioning, BANKING industry
Abstract

Brucella ovis is an etiologic agent of ovine epididymitis and brucellosis that causes global devastation in sheep, rams, goats, small ruminants and deer. There are no cost‐effective methods for the worldwide eradication of ovine brucellosis. B. ovis and other protein targets from various Brucella species are currently in the pipeline for high‐throughput structural analysis at the Seattle Structural Genomics Center for Infectious Disease (SSGCID), with the aim of identifying new therapeutic targets. Furthermore, the wealth of structures generated are effective tools for teaching scientific communication, structural science and biochemistry. One of these structures, B. ovis leucine‐, isoleucine‐, valine‐, threonine‐ and alanine‐binding protein (BoLBP), is a putative periplasmic amino acid‐binding protein. BoLBP shares less than 29% sequence identity with any other structure in the Protein Data Bank. The production, crystallization and high‐resolution structures of BoLBP are reported. BoLBP is a prototypical bacterial periplasmic amino acid‐binding protein with the characteristic Venus flytrap topology of two globular domains encapsulating a large central cavity containing the peptide‐binding region. The central cavity contains small molecules usurped from the crystallization milieu. The reported structures reveal the conformational flexibility of the central cavity in the absence of bound peptides. The structural similarity to other LBPs can be exploited to accelerate drug repurposing. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Author

Baragan˜a, Beatriz, Forte, Barbara, Choi, Ryan, Hewitt, Stephen Nakazawa, Bueren-Calabuig, Juan A., Pisco, Joa˜o Pedro, Peet, Caroline, Dranow, David M., Robinson, David A., Jansen, Chimed, Norcross, Neil R., Vinayak, Sumiti, Anderson, Mark, Brooks, Carrie F., Cooper, Caitlin A., Damerow, Sebastian, Delves, Michael, Dowers, Karen, Duffy, James, Edwards, Thomas E., Hallyburton, Irene, Horst, Benjamin G., Hulverson, Matthew A., Ferguson, Liam, Jiménez-Díaz, María Belén, Jumani, Rajiv S., Lorimer, Donald D., Love, Melissa S., Maher, Steven, Matthews, Holly, McNamara, Case W., Miller, Peter, O’Neill, Sandra, Ojo, Kayode K., Osuna-Cabello, Maria, Pinto, Erika, Post, John, Riley, Jennifer, Rottmann, Matthias, Sanz, Laura M., Scullion, Paul, Sharma, Arvind, Shepherd, Sharon M., Shishikura, Yoko, Simeons, Frederick R. C., Stebbins, Erin E., Stojanovski, Laste, Straschil, Ursula, Tamaki, Fabio K., Tamjar, Jevgenia, Torrie, Leah S., Vantaux, Amélie, Witkowski, Benoît, Wittlin, Sergio, Yogavel, Manickam, Zuccotto, Fabio, Angulo-Barturen, Iñigo, Sinden, Robert, Baum, Jake, Gamo, Francisco-Javier, Mäser, Pascal, Kyle, Dennis E., Winzeler, Elizabeth A., Myler, Peter J., Wyatt, Paul G., Floyd, David, Matthews, David, Sharma, Amit, Striepen, Boris, Huston, Christopher D., Gray, David W., Fairlamb, Alan H., Pisliakov, Andrei V., Walpole, Chris, Read, Kevin D., Van Voorhis, Wesley C., and Gilbert, Ian H.

Published
2019

19. In silico detection of SARS-CoV-2 specific B-cell epitopes and validation in ELISA for serological diagnosis of COVID-19

Author

Phan, Isabelle Q., Subramanian, Sandhya, Kim, David, Murphy, Michael, Pettie, Deleah, Carter, Lauren, Anishchenko, Ivan, Barrett, Lynn K., Craig, Justin, Tillery, Logan, Shek, Roger, Harrington, Whitney E., Koelle, David M., Wald, Anna, Veesler, David, King, Neil, Boonyaratanakornkit, Jim, Isoherranen, Nina, Greninger, Alexander L., Jerome, Keith R., Chu, Helen, Staker, Bart, Stewart, Lance, Myler, Peter J., and Van Voorhis, Wesley C.

Published
2021
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20. The Genome of the Kinetoplastid Parasite, Leishmania major

Author

Ivens, Alasdair C., Peacock, Christopher S., Worthey, Elizabeth A., Murphy, Lee, Aggarwal, Gautam, Berriman, Matthew, Sisk, Ellen, Rajandream, Marie-Adele, Adlem, Ellen, Aert, Rita, Anupama, Atashi, Apostolou, Zina, Attipoe, Philip, Bason, Nathalie, Bauser, Christopher, Beck, Alfred, Beverley, Stephen M., Bianchettin, Gabriella, Borzym, Katja, Bothe, Gordana, Bruschi, Carlo V., Collins, Matt, Cadag, Eithon, Ciarloni, Laura, Clayton, Christine, Cronin, Ann, Cruz, Angela K., Davies, Robert M., De Gaudenzi, Javier, Dobson, Deborah E., Duesterhoeft, Andreas, Fazelina, Gholam, Fosker, Nigel, Frasch, Alberto Carlos, Fraser, Audrey, Fuchs, Monika, Gabel, Claudia, Goble, Arlette, Goffeau, André, Harris, David, Hertz-Fowler, Christiane, Hilbert, Helmut, Horn, David, Huang, Yiting, Klages, Sven, Knights, Andrew, Kube, Michael, Larke, Natasha, Litvin, Lyudmila, Lord, Angela, Louie, Tin, Marra, Marco, Masuy, David, Matthews, Keith, Michaeli, Shulamit, Mottram, Jeremy C., Müller-Auer, Silke, Munden, Heather, Nelson, Siri, Norbertczak, Halina, Oliver, Karen, O'Neil, Susan, Pentony, Martin, Pohl, Thomas M., Price, Claire, Purnelle, Bénédicte, Quail, Michael A., Rabbinowitsch, Ester, Reinhardt, Richard, Rieger, Michael, Rinta, Joel, Robben, Johan, Robertson, Laura, Ruiz, Jeronimo C., Rutter, Simon, Saunders, David, Schäfer, Melanie, Schein, Jacquie, Schwartz, David C., Seeger, Kathy, Seyler, Amber, Sharp, Sarah, Shin, Heesun, Sivam, Dhileep, Squares, Rob, Squares, Steve, Tosato, Valentina, Vogt, Christy, Volckaert, Guido, Wambutt, Rolf, Warren, Tim, Wedler, Holger, Woodward, John, Zhou, Shiguo, Zimmermann, Wolfgang, Smith, Deborah F., Blackwell, Jenefer M., Stuart, Kenneth D., Barrell, Bart, and Myler, Peter J.

Published
2005

21. Comparative Genomics of Trypanosomatid Parasitic Protozoa

Author

El-Sayed, Najib M., Myler, Peter J., Blandin, Gaëlle, Berriman, Matthew, Crabtree, Jonathan, Aggarwal, Gautam, Caler, Elisabet, Renauld, Hubert, Worthey, Elizabeth A., Hertz-Fowler, Christiane, Ghedin, Elodie, Peacock, Christopher, Bartholomeu, Daniella C., Haas, Brian J., Tran, Anh-Nhi, Wortman, Jennifer R., Angiuoli, Samuel, Anupama, Atashi, Badger, Jonathan, Bringaud, Frederic, Cadag, Eithon, Carlton, Jane M., Cerqueira, Gustavo C., Creasy, Todd, Delcher, Arthur L., Djikeng, Appolinaire, Embley, T. Martin, Hauser, Christopher, Ivens, Alasdair C., Kummerfeld, Sarah K., Pereira-Leal, Jose B., Nilsson, Daniel, Peterson, Jeremy, Salzberg, Steven L., Shallom, Joshua, Silva, Joana C., Sundaram, Jaideep, Westenberger, Scott, White, Owen, Melville, Sara E., Donelson, John E., Andersson, Björn, Stuart, Kenneth D., and Hall, Neil

Published
2005

22. The Genome Sequence of Trypanosoma cruzi, Etiologic Agent of Chagas Disease

Author

El-Sayed, Najib M., Myler, Peter J., Bartholomeu, Daniella C., Nilsson, Daniel, Aggarwal, Gautam, Tran, Anh-Nhi, Ghedin, Elodie, Worthey, Elizabeth A., Delcher, Arthur L., Blandin, Gaëlle, Westenberger, Scott J., Caler, Elisabet, Cerqueira, Gustavo C., Anupama, Atashi, Arner, Erik, Åslund, Lena, Attipoe, Philip, Bontempi, Esteban, Bringaud, Frédéric, Burton, Peter, Cadag, Eithon, Campbell, David A., Carrington, Mark, Crabtree, Jonathan, Darban, Hamid, da Silveira, Jose Franco, de Jong, Pieter, Edwards, Kimberly, Englund, Paul T., Fazelina, Gholam, Feldblyum, Tamara, Ferella, Marcela, Frasch, Alberto Carlos, Gull, Keith, Horn, David, Hou, Lihua, Huang, Yiting, Kindlund, Ellen, Klingbeil, Michele, Kluge, Sindy, Koo, Hean, Lacerda, Daniela, Levin, Mariano J., Lorenzi, Hernan, Louie, Tin, Machado, Carlos Renato, McCulloch, Richard, McKenna, Alan, Mizuno, Yumi, Mottram, Jeremy C., Nelson, Siri, Ochaya, Stephen, Osoegawa, Kazutoyo, Pai, Grace, Parsons, Marilyn, Pentony, Martin, Pettersson, Ulf, Pop, Mihai, Ramirez, Jose Luis, Rinta, Joel, Robertson, Laura, Salzberg, Steven L., Sanchez, Daniel O., Seyler, Amber, Sharma, Reuben, Shetty, Jyoti, Simpson, Anjana J., Sisk, Ellen, Tammi, Martti T., Tarleton, Rick, Teixeira, Santuza, Van Aken, Susan, Vogt, Christy, Ward, Pauline N., Wickstead, Bill, Wortman, Jennifer, White, Owen, Fraser, Claire M., Stuart, Kenneth D., and Andersson, Björn

Published
2005

24. A divergent protein kinase A regulatory subunit essential for morphogenesis of the human pathogen Leishmania.

Author

Fischer Weinberger, Renana, Bachmaier, Sabine, Ober, Veronica, Githure, George B., Dandugudumula, Ramu, Phan, Isabelle Q., Almoznino, Michal, Polatoglou, Eleni, Tsigankov, Polina, Nitzan Koren, Roni, Myler, Peter J., Boshart, Michael, and Zilberstein, Dan

Subjects
PROTEIN kinases, CELL morphology, SAND flies, MAMMAL parasites, INTRACELLULAR pathogens, LEISHMANIA mexicana, LEISHMANIA, MORPHOGENESIS
Abstract

Parasitic protozoa of the genus Leishmania cycle between the phagolysosome of mammalian macrophages, where they reside as rounded intracellular amastigotes, and the midgut of female sand flies, which they colonize as elongated extracellular promastigotes. Previous studies indicated that protein kinase A (PKA) plays an important role in the initial steps of promastigote differentiation into amastigotes. Here, we describe a novel regulatory subunit of PKA (which we have named PKAR3) that is unique to Leishmania and most (but not all) other Kinetoplastidae. PKAR3 is localized to subpellicular microtubules (SPMT) in the cell cortex, where it recruits a specific catalytic subunit (PKAC3). Promastigotes of pkar3 or pkac3 null mutants lose their elongated shape and become rounded but remain flagellated. Truncation of an N-terminal formin homology (FH)-like domain of PKAR3 results in its detachment from the SPMT, also leading to rounded promastigotes. Thus, the tethering of PKAC3 via PKAR3 at the cell cortex is essential for maintenance of the elongated shape of promastigotes. This role of PKAR3 is reminiscent of PKARIβ and PKARIIβ binding to microtubules of mammalian neurons, which is essential for the elongation of dendrites and axons, respectively. Interestingly, PKAR3 binds nucleoside analogs, but not cAMP, with a high affinity similar to the PKAR1 isoform of Trypanosoma. We propose that these early-diverged protists have re-purposed PKA for a novel signaling pathway that spatiotemporally controls microtubule remodeling and cell shape. Author summary: Leishmania are single cell intracellular parasites of mammals, including humans. During their life, they cycle between macrophage phagolysosomes where they reside as rounded amastigotes, and the midgut of female sand flies, which they colonize as elongated promastigotes. Adaptation of Leishmania parasites to life in their mammalian host includes differentiation-associated changes in morphology from elongated promastigotes to rounded amastigotes. This study shows that a novel trypanosomatid-specific protein kinase A regulatory subunit (PKAR3) is essential for maintenance of the elongated shape of Leishmania promastigotes. PKAR3 is anchored to the subpellicular microtubule in the cell cortex by an N-terminal formin homology (FH)-like domain; where it recruits a developmentally regulated catalytic subunit (PKAC3). Exposure to the differentiation signal results in a rapid downregulation of PKA activity and subsequently cell rounding. Thus, the cAMP-independent PKAR3 appears to have been repurposed to serve an AKAP-like role in spatiotemporal control of morphogenesis, highlighting the evolutionary diversity of this family of signalling proteins. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Crystal structure and biophysical characterization of IspD from Burkholderia thailandensis and Mycobacterium paratuberculosis.

Author

Pierce, Phillip G., Hartnett, Brian E., Laughlin, Tosha M., Blain, Joy M., Mayclin, Stephen J., Bolejack, Madison J., Myers, Janette B., Higgins, Tate W., Dranow, David M., Sullivan, Amy, Lorimer, Donald D., Edwards, Thomas E., Hagen, Timothy J., Horn, James R., and Myler, Peter J.

Subjects
MYCOBACTERIUM avium paratuberculosis, CRYSTAL structure, BURKHOLDERIA, ISOTHERMAL titration calorimetry, ANTI-infective agents
Abstract

The methylerythritol phosphate (MEP) pathway is a metabolic pathway that produces the isoprenoids isopentyl pyrophosphate and dimethylallyl pyrophosphate. Notably, the MEP pathway is present in bacteria and not in mammals, which makes the enzymes of the MEP pathway attractive targets for discovering new anti‐infective agents due to the reduced chances of off‐target interactions leading to side effects. There are seven enzymes in the MEP pathway, the third of which is IspD. Two crystal structures of Burkholderia thailandensis IspD (BtIspD) were determined: an apo structure and that of a complex with cytidine triphosphate (CTP). Comparison of the CTP‐bound BtIspD structure with the apo structure revealed that CTP binding stabilizes the loop composed of residues 13–19. The apo structure of Mycobacterium paratuberculosis IspD (MpIspD) is also reported. The melting temperatures of MpIspD and BtIspD were evaluated by circular dichroism. The moderate Tm values suggest that a thermal shift assay may be feasible for future inhibitor screening. Finally, the binding affinity of CTP for BtIspD was evaluated by isothermal titration calorimetry. These structural and biophysical data will aid in the discovery of IspD inhibitors. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Increasing the structural coverage of tuberculosis drug targets

Author

Baugh, Loren, Phan, Isabelle, Begley, Darren W., Clifton, Matthew C., Armour, Brianna, Dranow, David M., Taylor, Brandy M., Muruthi, Marvin M., Abendroth, Jan, Fairman, James W., Fox, David, III, Dieterich, Shellie H., Staker, Bart L., Gardberg, Anna S., Choi, Ryan, Hewitt, Stephen N., Napuli, Alberto J., Myers, Janette, Barrett, Lynn K., Zhang, Yang, Ferrell, Micah, Mundt, Elizabeth, Thompkins, Katie, Tran, Ngoc, Lyons-Abbott, Sally, Abramov, Ariel, Sekar, Aarthi, Serbzhinskiy, Dmitri, Lorimer, Don, Buchko, Garry W., Stacy, Robin, Stewart, Lance J., Edwards, Thomas E., Van Voorhis, Wesley C., and Myler, Peter J.

Published
2015
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37. Bunyavirales: Scientific Gaps and Prototype Pathogens for a Large and Diverse Group of Zoonotic Viruses.

Author

Hartman, Amy L and Myler, Peter J

Subjects
*ANIMAL disease models, *LIFE cycles (Biology), *VACCINE trials, *REVERSE genetics, *PROTOTYPES
Abstract

Research directed at select prototype pathogens is part of the approach put forth by the National Institute of Allergy and Infectious Disease (NIAID) to prepare for future pandemics caused by emerging viruses. We were tasked with identifying suitable prototypes for four virus families of the Bunyavirales order (Phenuiviridae , Peribunyaviridae , Nairoviridae , and Hantaviridae). This is a challenge due to the breadth and diversity of these viral groups. While there are many differences among the Bunyavirales , they generally have complex ecological life cycles, segmented genomes, and cause a range of human clinical outcomes from mild to severe and even death. Here, we delineate potential prototype species that encompass the breadth of clinical outcomes of a given family, have existing reverse genetics tools or animal disease models, and can be amenable to a platform approach to vaccine testing. Suggested prototype pathogens outlined here can serve as a starting point for further discussions. [ABSTRACT FROM AUTHOR]

Published
2023
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39. Characterization of a family I inorganic pyrophosphatase from Legionella pneumophila Philadelphia 1.

Author

Moorefield, Julia, Konuk, Yagmur, Norman, Jordan O., Abendroth, Jan, Edwards, Thomas E., Lorimer, Donald D., Mayclin, Stephen J., Staker, Bart L., Craig, Justin K., Barett, Kayleigh F., Barrett, Lynn K., Van Voorhis, Wesley C., Myler, Peter J., and McLaughlin, Krystle J.

Subjects
LEGIONELLA pneumophila, INORGANIC pyrophosphatase, LEGIONNAIRES' disease, FAMILY structure, RNA synthesis
Abstract

Inorganic pyrophosphate (PPi) is generated as an intermediate or byproduct of many fundamental metabolic pathways, including DNA/RNA synthesis. The intracellular concentration of PPi must be regulated as buildup can inhibit many critical cellular processes. Inorganic pyrophosphatases (PPases) hydrolyze PPi into two orthophosphates (Pi), preventing the toxic accumulation of the PPi byproduct in cells and making Pi available for use in biosynthetic pathways. Here, the crystal structure of a family I inorganic pyrophosphatase from Legionella pneumophila is reported at 2.0 Å resolution. L. pneumophila PPase (LpPPase) adopts a homohexameric assembly and shares the oligonucleotide/oligosaccharide‐binding (OB) β‐barrel core fold common to many other bacterial family I PPases. LpPPase demonstrated hydrolytic activity against a general substrate, with Mg2+ being the preferred metal cofactor for catalysis. Legionnaires' disease is a severe respiratory infection caused primarily by L. pneumophila, and thus increased characterization of the L. pneumophila proteome is of interest. [ABSTRACT FROM AUTHOR]

Published
2023
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