39 results on '"Nguyen, Henry C."'
Search Results
2. Mechanism of a rabbit monoclonal antibody broadly neutralizing SARS-CoV-2 variants
- Author
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Guo, Hangtian, Yang, Yixuan, Zhao, Tiantian, Lu, Yuchi, Gao, Yan, Li, Tinghan, Xiao, Hang, Chu, Xiaoyu, Zheng, Le, Li, Wanting, Cheng, Hao, Huang, Haibin, Liu, Yang, Lou, Yang, Nguyen, Henry C., Wu, Chao, Chen, Yuxin, Yang, Haitao, and Ji, Xiaoyun
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- 2023
- Full Text
- View/download PDF
3. CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes
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Gupta, Meghna, Azumaya, Caleigh M, Moritz, Michelle, Pourmal, Sergei, Diallo, Amy, Merz, Gregory E, Jang, Gwendolyn, Bouhaddou, Mehdi, Fossati, Andrea, Brilot, Axel F, Diwanji, Devan, Hernandez, Evelyn, Herrera, Nadia, Kratochvil, Huong T, Lam, Victor L, Li, Fei, Li, Yang, Nguyen, Henry C, Nowotny, Carlos, Owens, Tristan W, Peters, Jessica K, Rizo, Alexandrea N, Schulze-Gahmen, Ursula, Smith, Amber M, Young, Iris D, Yu, Zanlin, Asarnow, Daniel, Billesbølle, Christian, Campbell, Melody G, Chen, Jen, Chen, Kuei-Ho, Chio, Un Seng, Dickinson, Miles Sasha, Doan, Loan, Jin, Mingliang, Kim, Kate, Li, Junrui, Li, Yen-Li, Linossi, Edmond, Liu, Yanxin, Lo, Megan, Lopez, Jocelyne, Lopez, Kyle E, Mancino, Adamo, Moss, Frank R, Paul, Michael D, Pawar, Komal Ishwar, Pelin, Adrian, Pospiech, Thomas H, Puchades, Cristina, Remesh, Soumya Govinda, Safari, Maliheh, Schaefer, Kaitlin, Sun, Ming, Tabios, Mariano C, Thwin, Aye C, Titus, Erron W, Trenker, Raphael, Tse, Eric, Tsui, Tsz Kin Martin, Wang, Feng, Zhang, Kaihua, Zhang, Yang, Zhao, Jianhua, Zhou, Fengbo, Zhou, Yuan, Zuliani-Alvarez, Lorena, Consortium, QCRG Structural Biology, Agard, David A, Cheng, Yifan, Fraser, James S, Jura, Natalia, Kortemme, Tanja, Manglik, Aashish, Southworth, Daniel R, Stroud, Robert M, Swaney, Danielle L, Krogan, Nevan J, Frost, Adam, Rosenberg, Oren S, and Verba, Kliment A
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Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Biological Sciences ,Pneumonia ,Emerging Infectious Diseases ,Biodefense ,Vaccine Related ,Infectious Diseases ,Prevention ,Pneumonia & Influenza ,Lung ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Infection ,Generic health relevance - Abstract
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
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- 2021
4. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2
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Azumaya, Caleigh M, Braxton, Julian R, Brilot, Axel F, Gupta, Meghna, Li, Fei, Lopez, Kyle E, Melo, Arthur, Merz, Gregory E, Moss, Frank, Paulino, Joana, Pospiech, Thomas H, Pourmal, Sergei, Puchades, Cristina, Rizo, Alexandrea N, Smith, Amber M, Sun, Ming, Thomas, Paul V, Wang, Feng, Yu, Zanlin, Asarnow, Daniel, Campbell, Melody G, Chio, Cynthia M, Chio, Un Seng, Dickinson, Miles Sasha, Diwanji, Devan, Faust, Bryan, Hoppe, Nick, Jin, Mingliang, Li, Junrui, Liu, Yanxin, Nguyen, Henry C, Sangwan, Smriti, Trenker, Raphael, Trinidad, Donovan, Tse, Eric, Zhang, Kaihua, Zhou, Fengbo, Billesboelle, Christian, Bowen, Alisa, Li, Yen-Li, Nguyen, Phuong, Nowotny, Carlos, Safari, Mali, Schaefer, Kaitlin, Tsui, Tsz Kin Martin, Whitis, Natalie, Zhao, Jianhua, Kim, Kate, Moritz, Michelle, Owens, Tristan W, Peters, Jessica K, Biel, Justin, Deshpande, Ishan, Herrera, Nadia, Kratochvil, Huong T, Liu, Xi, Schulze-Gahmen, Ursula, Young, Iris D, Chen, Jen, Diallo, Amy, Doan, Loan, Flores, Sebastian, Lam, Victor L, Li, Yang, Lo, Megan, Thwin, Aye C, Titus, Erron W, Zhang, Yang, and Bulkley, David
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Biological Sciences ,Bioinformatics and Computational Biology ,Biodefense ,Vaccine Related ,Clinical Research ,Prevention ,Lung ,Emerging Infectious Diseases ,Infectious Diseases ,Pneumonia & Influenza ,Pneumonia ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Angiotensin-Converting Enzyme 2 ,Animals ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Binding Sites ,Antibody ,Chlorocebus aethiops ,Cryoelectron Microscopy ,HEK293 Cells ,Humans ,Models ,Molecular ,Peptide Library ,Protein Binding ,Protein Conformation ,alpha-Helical ,Protein Conformation ,beta-Strand ,Protein Interaction Domains and Motifs ,SARS-CoV-2 ,Single-Chain Antibodies ,Spike Glycoprotein ,Coronavirus ,Vero Cells ,QCRG Structural Biology Consortium ,Medicinal and Biomolecular Chemistry ,Biochemistry and Cell Biology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.
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- 2021
5. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
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Schoof, Michael, Faust, Bryan, Saunders, Reuben A, Sangwan, Smriti, Rezelj, Veronica, Hoppe, Nick, Boone, Morgane, Billesbølle, Christian B, Puchades, Cristina, Azumaya, Caleigh M, Kratochvil, Huong T, Zimanyi, Marcell, Deshpande, Ishan, Liang, Jiahao, Dickinson, Sasha, Nguyen, Henry C, Chio, Cynthia M, Merz, Gregory E, Thompson, Michael C, Diwanji, Devan, Schaefer, Kaitlin, Anand, Aditya A, Dobzinski, Niv, Zha, Beth Shoshana, Simoneau, Camille R, Leon, Kristoffer, White, Kris M, Chio, Un Seng, Gupta, Meghna, Jin, Mingliang, Li, Fei, Liu, Yanxin, Zhang, Kaihua, Bulkley, David, Sun, Ming, Smith, Amber M, Rizo, Alexandrea N, Moss, Frank, Brilot, Axel F, Pourmal, Sergei, Trenker, Raphael, Pospiech, Thomas, Gupta, Sayan, Barsi-Rhyne, Benjamin, Belyy, Vladislav, Barile-Hill, Andrew W, Nock, Silke, Liu, Yuwei, Krogan, Nevan J, Ralston, Corie Y, Swaney, Danielle L, García-Sastre, Adolfo, Ott, Melanie, Vignuzzi, Marco, Walter, Peter, Manglik, Aashish, Braxton, Julian R, Lopez, Kyle E, Melo, Arthur, Paulino, Joana, Pospiech, Thomas H, Thomas, Paul V, Wang, Feng, Yu, Zanlin, Dickinson, Miles Sasha, Asarnow, Daniel, Campbell, Melody G, Li, Junrui, Tsui, Tsz Kin Martin, Trinidad, Donovan, Tse, Eric, Zhou, Fengbo, Herrera, Nadia, and Schulze-Gahmen, Ursula
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Biochemistry and Cell Biology ,Biological Sciences ,Lung ,Vaccine Related ,Prevention ,Infectious Diseases ,Pneumonia ,Pneumonia & Influenza ,Biodefense ,Emerging Infectious Diseases ,Angiotensin-Converting Enzyme 2 ,Animals ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Antibody Affinity ,Chlorocebus aethiops ,Cryoelectron Microscopy ,Humans ,Neutralization Tests ,Protein Binding ,Protein Stability ,Single-Domain Antibodies ,Spike Glycoprotein ,Coronavirus ,Vero Cells ,QCRG Structural Biology Consortium ,General Science & Technology - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
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- 2020
6. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms
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Gordon, David E, Hiatt, Joseph, Bouhaddou, Mehdi, Rezelj, Veronica V, Ulferts, Svenja, Braberg, Hannes, Jureka, Alexander S, Obernier, Kirsten, Guo, Jeffrey Z, Batra, Jyoti, Kaake, Robyn M, Weckstein, Andrew R, Owens, Tristan W, Gupta, Meghna, Pourmal, Sergei, Titus, Erron W, Cakir, Merve, Soucheray, Margaret, McGregor, Michael, Cakir, Zeynep, Jang, Gwendolyn, O’Meara, Matthew J, Tummino, Tia A, Zhang, Ziyang, Foussard, Helene, Rojc, Ajda, Zhou, Yuan, Kuchenov, Dmitry, Hüttenhain, Ruth, Xu, Jiewei, Eckhardt, Manon, Swaney, Danielle L, Fabius, Jacqueline M, Ummadi, Manisha, Tutuncuoglu, Beril, Rathore, Ujjwal, Modak, Maya, Haas, Paige, Haas, Kelsey M, Naing, Zun Zar Chi, Pulido, Ernst H, Shi, Ying, Barrio-Hernandez, Inigo, Memon, Danish, Petsalaki, Eirini, Dunham, Alistair, Marrero, Miguel Correa, Burke, David, Koh, Cassandra, Vallet, Thomas, Silvas, Jesus A, Azumaya, Caleigh M, Billesbølle, Christian, Brilot, Axel F, Campbell, Melody G, Diallo, Amy, Dickinson, Miles Sasha, Diwanji, Devan, Herrera, Nadia, Hoppe, Nick, Kratochvil, Huong T, Liu, Yanxin, Merz, Gregory E, Moritz, Michelle, Nguyen, Henry C, Nowotny, Carlos, Puchades, Cristina, Rizo, Alexandrea N, Schulze-Gahmen, Ursula, Smith, Amber M, Sun, Ming, Young, Iris D, Zhao, Jianhua, Asarnow, Daniel, Biel, Justin, Bowen, Alisa, Braxton, Julian R, Chen, Jen, Chio, Cynthia M, Chio, Un Seng, Deshpande, Ishan, Doan, Loan, Faust, Bryan, Flores, Sebastian, Jin, Mingliang, Kim, Kate, Lam, Victor L, Li, Fei, Li, Junrui, Li, Yen-Li, Li, Yang, Liu, Xi, Lo, Megan, Lopez, Kyle E, Melo, Arthur A, Moss, Frank R, Nguyen, Phuong, Paulino, Joana, Pawar, Komal Ishwar, and Peters, Jessica K
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Biological Sciences ,Bioinformatics and Computational Biology ,Infectious Diseases ,Coronaviruses Therapeutics and Interventions ,Lung ,Coronaviruses ,Pneumonia ,Emerging Infectious Diseases ,Genetics ,Biodefense ,Pneumonia & Influenza ,Generic health relevance ,Infection ,Good Health and Well Being ,COVID-19 ,Conserved Sequence ,Coronavirus Nucleocapsid Proteins ,Cryoelectron Microscopy ,Host Microbial Interactions ,Humans ,Mitochondrial Membrane Transport Proteins ,Mitochondrial Precursor Protein Import Complex Proteins ,Phosphoproteins ,Protein Conformation ,Protein Interaction Maps ,Severe acute respiratory syndrome-related coronavirus ,SARS-CoV-2 ,Severe Acute Respiratory Syndrome ,QCRG Structural Biology Consortium ,Zoonomia Consortium ,General Science & Technology - Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
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- 2020
7. Membrane constriction and thinning by sequential ESCRT-III polymerization.
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Nguyen, Henry C, Talledge, Nathaniel, McCullough, John, Sharma, Abhimanyu, Moss, Frank R, Iwasa, Janet H, Vershinin, Michael D, Sundquist, Wesley I, and Frost, Adam
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Cell Membrane ,Endosomes ,Humans ,Membrane Proteins ,Oncogene Proteins ,Cytokinesis ,Protein Conformation ,Endosomal Sorting Complexes Required for Transport ,Polymerization ,Chemical Sciences ,Biological Sciences ,Medical and Health Sciences ,Biophysics ,Developmental Biology - Abstract
The endosomal sorting complexes required for transport (ESCRTs) mediate diverse membrane remodeling events. These typically require ESCRT-III proteins to stabilize negatively curved membranes; however, recent work has indicated that certain ESCRT-IIIs also participate in positive-curvature membrane-shaping reactions. ESCRT-IIIs polymerize into membrane-binding filaments, but the structural basis for negative versus positive membrane remodeling by these proteins remains poorly understood. To learn how certain ESCRT-IIIs shape positively curved membranes, we determined structures of human membrane-bound CHMP1B-only, membrane-bound CHMP1B + IST1, and IST1-only filaments by cryo-EM. Our structures show how CHMP1B first polymerizes into a single-stranded helical filament, shaping membranes into moderate-curvature tubules. Subsequently, IST1 assembles a second strand on CHMP1B, further constricting the membrane tube and reducing its diameter nearly to the fission point. Each step of constriction thins the underlying bilayer, lowering the barrier to membrane fission. Our structures reveal how a two-component, sequential polymerization mechanism drives membrane tubulation, constriction and bilayer thinning.
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- 2020
8. IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity
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Moynihan, Kelly D., primary, Kumar, Manu P., additional, Sultan, Hussein, additional, Pappas, Danielle C., additional, Park, Terrence, additional, Chin, S. Michael, additional, Bessette, Paul, additional, Lan, Ruth Y., additional, Nguyen, Henry C., additional, Mathewson, Nathan D., additional, Ni, Irene, additional, Chen, Wei, additional, Lee, Yonghee, additional, Liao-Chan, Sindy, additional, Chen, Jessie, additional, Schumacher, Ton N.M., additional, Schreiber, Robert D., additional, Yeung, Yik A., additional, and Djuretic, Ivana M., additional
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- 2024
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9. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response
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Kenner, Lillian R, Anand, Aditya A, Nguyen, Henry C, Myasnikov, Alexander G, Klose, Carolin J, McGeever, Lea A, Tsai, Jordan C, Miller-Vedam, Lakshmi E, Walter, Peter, and Frost, Adam
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Generic health relevance ,Cryoelectron Microscopy ,Enzyme Activation ,Enzymes ,Eukaryotic Initiation Factor-2 ,Eukaryotic Initiation Factor-2B ,Guanine Nucleotides ,Humans ,Models ,Chemical ,Phosphorylation ,Protein Biosynthesis ,Protein Conformation ,Protein Multimerization ,Stress ,Physiological ,General Science & Technology - Abstract
The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.
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- 2019
10. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
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Tsai, Jordan C, Miller-Vedam, Lakshmi E, Anand, Aditya A, Jaishankar, Priyadarshini, Nguyen, Henry C, Renslo, Adam R, Frost, Adam, and Walter, Peter
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Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Acetamides ,Cryoelectron Microscopy ,Cyclohexylamines ,Escherichia coli ,Eukaryotic Initiation Factor-2B ,Humans ,Memory ,Mutation ,Nootropic Agents ,Phosphorylation ,Protein Conformation ,Protein Folding ,Protein Multimerization ,Protein Stability ,Recombinant Proteins ,General Science & Technology - Abstract
Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.
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- 2018
11. CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus
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Andreata, Francesco, primary, Moynihan, Kelly D., additional, Fumagalli, Valeria, additional, Di Lucia, Pietro, additional, Pappas, Danielle C., additional, Kawashima, Keigo, additional, Ni, Irene, additional, Bessette, Paul H., additional, Perucchini, Chiara, additional, Bono, Elisa, additional, Giustini, Leonardo, additional, Nguyen, Henry C., additional, Chin, S. Michael, additional, Yeung, Yik Andy, additional, Gibbs, Craig S., additional, Djuretic, Ivana, additional, and Iannacone, Matteo, additional
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- 2024
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12. Elucidating substrate binding in the light-dependent protochlorophyllide oxidoreductase
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Pesara, Penelope, primary, Szafran, Katarzyna, additional, Nguyen, Henry C., additional, Sirohiwal, Abhishek, additional, Pantazis, Dimitrios A., additional, and Gabruk, Michal, additional
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- 2024
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13. Photocatalytic LPOR forms helical lattices that shape membranes for chlorophyll synthesis
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Nguyen, Henry C., Melo, Arthur A., Kruk, Jerzy, Frost, Adam, and Gabruk, Michal
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- 2021
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14. Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity
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Zheng, Le, primary, Yang, Tingting, additional, Guo, Hangtian, additional, Qi, Chen, additional, Lu, Yuchi, additional, Xiao, Haonan, additional, Gao, Yan, additional, Liu, Yue, additional, Yang, Yixuan, additional, Zhou, Mengru, additional, Nguyen, Henry C., additional, Zhu, Yun, additional, Sun, Fei, additional, Zhang, Chen-yu, additional, and Ji, Xiaoyun, additional
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- 2023
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15. Structural basis of antagonism of human APOBEC3F by HIV-1 Vif
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Hu, Yingxia, Desimmie, Belete A., Nguyen, Henry C., Ziegler, Samantha J., Cheng, Tat Cheung, Chen, John, Wang, Jia, Wang, Hongwei, Zhang, Kai, Pathak, Vinay K., and Xiong, Yong
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- 2019
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16. Pigment Binding in The Light-Dependent Protochlorophyllide Oxidoreductase
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Pesara, Penelope, primary, Szafran, Katarzyna, additional, Nguyen, Henry C, additional, Sirohiwal, Abhishek, additional, Pantazis, Dimitrios A., additional, and Gabruk, Michal, additional
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- 2023
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17. Cullin-RING E3 Ubiquitin Ligases: Bridges to Destruction
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Nguyen, Henry C., Wang, Wei, Xiong, Yong, Harris, J. Robin, Series editor, and Marles-Wright, Jon, editor
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- 2017
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18. Structural Insight Into hnRNP A2/B1 Homodimerization and DNA Recognition
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Liu, Yue, primary, Abula, Abudureyimu, additional, Xiao, Haonan, additional, Guo, Hangtian, additional, Li, Tinghan, additional, Zheng, Le, additional, Chen, Biqing, additional, Nguyen, Henry C., additional, and Ji, Xiaoyun, additional
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- 2023
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19. Crystal structure of monkeypox H1 phosphatase, an antiviral drug target.
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Cui, Wen, Huang, Haojun, Duan, Yinkai, Luo, Zhi, Wang, Haofeng, Zhang, Tenan, Nguyen, Henry C, Shen, Wei, Su, Dan, Li, Xi, Ji, Xiaoyun, Yang, Haitao, and Wang, Wei
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- 2023
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20. Crystal structure of monkeypox H1 phosphatase, an antiviral drug target
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Cui, Wen, primary, Huang, Haojun, additional, Duan, Yinkai, additional, Luo, Zhi, additional, Wang, Haofeng, additional, Zhang, Tenan, additional, Nguyen, Henry C, additional, Shen, Wei, additional, Su, Dan, additional, Li, Xi, additional, Ji, Xiaoyun, additional, Yang, Haitao, additional, and Wang, Wei, additional
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- 2022
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21. Structures of Omicron spike complexes and implications for neutralizing antibody development
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Guo, Hangtian, primary, Gao, Yan, additional, Li, Tinghan, additional, Li, Tingting, additional, Lu, Yuchi, additional, Zheng, Le, additional, Liu, Yue, additional, Yang, Tingting, additional, Luo, Feiyang, additional, Song, Shuyi, additional, Wang, Wei, additional, Yang, Xiuna, additional, Nguyen, Henry C., additional, Zhang, Hongkai, additional, Huang, Ailong, additional, Jin, Aishun, additional, Yang, Haitao, additional, Rao, Zihe, additional, and Ji, Xiaoyun, additional
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- 2022
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22. Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity
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Zheng, Le, Yang, Tingting, Guo, Hangtian, Qi, Chen, Lu, Yuchi, Xiao, Haonan, Gao, Yan, Liu, Yue, Yang, Yixuan, Zhou, Mengru, Nguyen, Henry C., Zhu, Yun, Sun, Fei, Zhang, Chen-Yu, and Ji, Xiaoyun
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- 2023
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23. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms
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Gordon, David E., Hiatt, Joseph, Bouhaddou, Mehdi, Rezelj, Veronica V., Ulferts, Svenja, Braberg, Hannes, Jureka, Alexander S., Obernier, Kirsten, Guo, Jeffrey Z., Batra, Jyoti, Kaake, Robyn M., Weckstein, Andrew R., Owens, Tristan W., Gupta, Meghna, Pourmal, Sergei, Titus, Erron W., Cakir, Merve, Soucheray, Margaret, McGregor, Michael, Cakir, Zeynep, Jang, Gwendolyn, O’Meara, Matthew J., Zhang, Ziyang, Foussard, Helene, Rojc, Ajda, Zhou, Yuan, Kuchenov, Dmitry, Hüttenhain, Ruth, Xu, Jiewei, Eckhardt, Manon, Swaney, Danielle L., Fabius, Jacqueline M., Ummadi, Manisha, Tutuncuoglu, Beril, Rathore, Ujjwal, Modak, Maya, Haas, Paige, Haas, Kelsey M., Naing, Zun Zar Chi, Pulido, Ernst H., Shi, Ying, Barrio-Hernandez, Inigo, Memon, Danish, Petsalaki, Eirini, Dunham, Alistair, Correa Marrero, Miguel, Burke, David, Koh, Cassandra, Vallet, Thomas, Silvas, Jesus A., Azumaya, Caleigh M., Billesbølle, Christian, Brilot, Axel F., Campbell, Melody G., Diallo, Amy, Dickinson, Miles Sasha, Diwanji, Devan, Herrera, Nadia, Hoppe, Nick, Kratochvil, Huong T., Liu, Yanxin, Merz, Gregory E., Moritz, Michelle, Nguyen, Henry C., Nowotny, Carlos, Puchades, Cristina, Rizo, Alexandrea N., Schulze-Gahmen, Ursula, Smith, Amber M., Sun, Ming, Young, Iris D., Zhao, Jianhua, Asarnow, Daniel, Biel, Justin, Braxton, Julian R., Chen, Jen, Chio, Cynthia M., Chio, Un Seng, Deshpande, Ishan, Doan, Loan, Faust, Bryan, Flores, Sebastian, Jin, Mingliang, Kim, Kate, Lam, Victor L., Li, Fei, Li, Junrui, Li, Yen-Li, Li, Yang, Liu, Xi, Lo, Megan, Lopez, Kyle E., Melo, Arthur A., Nguyen, Phuong, Paulino, Joana, Pawar, Komal Ishwar, Peters, Jessica K., Pospiech, Thomas H., Safari, Maliheh, Sangwan, Smriti, Schaefer, Kaitlin, Thomas, Paul V., Thwin, Aye C., Trenker, Raphael, Tse, Eric, Tsui, Tsz Kin Martin, Wang, Feng, Whitis, Natalie, Yu, Zanlin, Zhang, Kaihua, Zhang, Yang, Zhou, Fengbo, Saltzberg, Daniel, QCRG Structural Biology Consortium, Hodder, Anthony J., Williams, Daniel M., White, Kris M., Rosales, Romel, Kehrer, Thomas, Miorin, Lisa, Moreno, Elena, Patel, Arvind H., Rihn, Suzannah, Khalid, Mir M., Vallejo-Gracia, Albert, Fozouni, Parinaz, Simoneau, Camille R., Roth, Theodore L., Wu, David, Karim, Mohd Anisul, Ghoussaini, Maya, Dunham, Ian, Berardi, Francesco, Weigang, Sebastian, Chazal, Maxime, Park, Jisoo, Logue, James, McGrath, Marisa, Weston, Stuart, Hastie, C. James, Elliott, Matthew, Brown, Fiona, Burness, Kerry A., Reid, Elaine, Dorward, Mark, Johnson, Clare, Wilkinson, Stuart G., Geyer, Anna, Giesel, Daniel M., Baillie, Carla, Raggett, Samantha, Leech, Hannah, Goodman, Nicola, Keough, Kathleen C., Lind, Abigail L., Zoonomia Consortium, Klesh, Reyna J., Hemphill, Kafi R., Carlson-Stevermer, Jared, Oki, Jennifer, Holden, Kevin, Maures, Travis, Pollard, Katherine S., Sali, Andrej, Agard, David A., Cheng, Yifan, Fraser, James S., Frost, Adam, Jura, Natalia, Kortemme, Tanja, Manglik, Aashish, Southworth, Daniel R., Stroud, Robert M., Alessi, Dario R., Davies, Paul, Frieman, Matthew B., Ideker, Trey, Abate, Carmen, Jouvenet, Nolwenn, Kochs, Georg, Shoichet, Brian, Ott, Melanie, Palmarini, Massimo, Shokat, Kevan M., García-Sastre, Adolfo, Rassen, Jeremy A., Grosse, Robert, Rosenberg, Oren S., Verba, Kliment A., Basler, Christopher F., Vignuzzi, Marco, Peden, Andrew A., Beltrao, Pedro, and Krogan, Nevan J.
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viruses ,virus diseases - Abstract
Introduction The emergence of three lethal coronaviruses in, Science, 370 (6521), ISSN:0036-8075, ISSN:1095-9203
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- 2020
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24. Photocatalytic plant LPOR forms helical lattices that shape membranes for chlorophyll synthesis
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Nguyen, Henry C., primary, Melo, Arthur A., additional, Kruk, Jerzy, additional, Frost, Adam, additional, and Gabruk, Michal, additional
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- 2020
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25. Membrane Constriction and Thinning by Sequential ESCRT-III Polymerization
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Nguyen, Henry C., primary, Talledge, Nathaniel, additional, McCullough, John, additional, Sharma, Abhimanyu, additional, Moss, Frank R., additional, Iwasa, Janet, additional, Vershinin, Michael, additional, Sundquist, Wesley I., additional, and Frost, Adam, additional
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- 2020
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26. Membrane constriction and thinning by sequential ESCRT-III polymerization
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Nguyen, Henry C., primary, Talledge, Nathaniel, additional, McCullough, John, additional, Sharma, Abhimanyu, additional, Moss, Frank R., additional, Iwasa, Janet H., additional, Vershinin, Michael D., additional, Sundquist, Wesley I., additional, and Frost, Adam, additional
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- 2019
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27. Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response
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Anand, Aditya A, primary, Kenner, Lillian R, additional, Nguyen, Henry C, additional, Myasnikov, Alexander G, additional, Klose, Carolin J, additional, McGeever, Lea A, additional, Tsai, Jordan C, additional, Miller-Vedam, Lakshmi E, additional, Walter, Peter, additional, and Frost, Adam, additional
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- 2018
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28. The ESCRT-III proteins IST1 and CHMP1B assemble around nucleic acids
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Talledge, Nathaniel, primary, McCullough, John, additional, Wenzel, Dawn, additional, Nguyen, Henry C., additional, Lalonde, Matthew S., additional, Bajorek, Monika, additional, Skalicky, Jack, additional, Frost, Adam, additional, and Sundqust, Wesley I., additional
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- 2018
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29. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
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Tsai, Jordan C., primary, Miller-Vedam, Lakshmi E., additional, Anand, Aditya A., additional, Jaishankar, Priyadarshini, additional, Nguyen, Henry C., additional, Renslo, Adam R., additional, Frost, Adam, additional, and Walter, Peter, additional
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- 2017
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30. FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy
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Al-Yacoub, Nadya, primary, Shaheen, Ranad, additional, Awad, Salma Mahmoud, additional, Kunhi, Muhammad, additional, Dzimiri, Nduna, additional, Nguyen, Henry C., additional, Xiong, Yong, additional, Al-Buraiki, Jehad, additional, Al-Habeeb, Waleed, additional, Alkuraya, Fowzan S., additional, and Poizat, Coralie, additional
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- 2016
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31. Insights into Cullin-RING E3 Ubiquitin Ligase Recruitment: Structure of the VHL-EloBC-Cul2 Complex
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Nguyen, Henry C., primary, Yang, Haitao, additional, Fribourgh, Jennifer L., additional, Wolfe, Leslie S., additional, and Xiong, Yong, additional
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- 2015
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32. Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families
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Alazami, Anas M., primary, Patel, Nisha, additional, Shamseldin, Hanan E., additional, Anazi, Shamsa, additional, Al-Dosari, Mohammed S., additional, Alzahrani, Fatema, additional, Hijazi, Hadia, additional, Alshammari, Muneera, additional, Aldahmesh, Mohammed A., additional, Salih, Mustafa A., additional, Faqeih, Eissa, additional, Alhashem, Amal, additional, Bashiri, Fahad A., additional, Al-Owain, Mohammed, additional, Kentab, Amal Y., additional, Sogaty, Sameera, additional, Al Tala, Saeed, additional, Temsah, Mohamad-Hani, additional, Tulbah, Maha, additional, Aljelaify, Rasha F., additional, Alshahwan, Saad A., additional, Seidahmed, Mohammed Zain, additional, Alhadid, Adnan A., additional, Aldhalaan, Hesham, additional, AlQallaf, Fatema, additional, Kurdi, Wesam, additional, Alfadhel, Majid, additional, Babay, Zainab, additional, Alsogheer, Mohammad, additional, Kaya, Namik, additional, Al-Hassnan, Zuhair N., additional, Abdel-Salam, Ghada M.H., additional, Al-Sannaa, Nouriya, additional, Al Mutairi, Fuad, additional, El Khashab, Heba Y., additional, Bohlega, Saeed, additional, Jia, Xiaofei, additional, Nguyen, Henry C., additional, Hammami, Rakad, additional, Adly, Nouran, additional, Mohamed, Jawahir Y., additional, Abdulwahab, Firdous, additional, Ibrahim, Niema, additional, Naim, Ewa A., additional, Al-Younes, Banan, additional, Meyer, Brian F., additional, Hashem, Mais, additional, Shaheen, Ranad, additional, Xiong, Yong, additional, Abouelhoda, Mohamed, additional, Aldeeri, Abdulrahman A., additional, Monies, Dorota M., additional, and Alkuraya, Fowzan S., additional
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- 2015
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33. Structural Insight into HIV-1 Restriction by MxB
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Fribourgh, Jennifer L., primary, Nguyen, Henry C., additional, Matreyek, Kenneth A., additional, Alvarez, Frances Joan D., additional, Summers, Brady J., additional, Dewdney, Tamaria G., additional, Aiken, Christopher, additional, Zhang, Peijun, additional, Engelman, Alan, additional, and Xiong, Yong, additional
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- 2014
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34. Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity
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Schrick, Kathrin, primary, Bruno, Michael, additional, Khosla, Aashima, additional, Cox, Paige N, additional, Marlatt, Sara A, additional, Roque, Remigio A, additional, Nguyen, Henry C, additional, He, Cuiwen, additional, Snyder, Michael P, additional, Singh, Daljit, additional, and Yadav, Gitanjali, additional
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- 2014
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35. Core Binding Factor Beta Plays a Critical Role by Facilitating the Assembly of the Vif-Cullin 5 E3 Ubiquitin Ligase
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Fribourgh, Jennifer L., primary, Nguyen, Henry C., additional, Wolfe, Leslie S., additional, DeWitt, David C., additional, Zhang, Wenyan, additional, Yu, Xiao-Fang, additional, Rhoades, Elizabeth, additional, and Xiong, Yong, additional
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- 2014
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36. Shared functions of plant and mammalian StARrelated lipid transfer (START) domains in modulating transcription factor activity.
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Schrick, Kathrin, Bruno, Michael, Khosla, Aashima, Cox, Paige N., Marlatt, Sara A., Roque, Remigio A., Nguyen, Henry C., He, Cuiwen, Snyder, Michael P., Singh, Daljit, and Yadav, Gitanjali
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STEROIDOGENIC acute regulatory protein ,LIPID transfer protein ,TRANSCRIPTION factors ,LEUCINE zippers ,PHENOTYPES - Abstract
Background Steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains were first identified from mammalian proteins that bind lipid/sterol ligands via a hydrophobic pocket. In plants, predicted START domains are predominantly found in homeodomain leucine zipper (HD-Zip) transcription factors that are master regulators of cell-type differentiation in development. Here we utilized studies in Arabidopsis in parallel with heterologous expression of START domains in yeast to investigate the hypothesis that START domains are versatile ligand-binding motifs that can modulate transcription factor activity. Results Our results show that deletion of the START domain from Arabidopsis GLABRA2 (GL2), a representative HD-Zip transcription factor involved in differentiation of the epidermis, results in a complete loss-of-function phenotype although the protein correctly localizes to the nucleus. Despite low sequence similarly, the mammalian START domain from StAR can functionally replace the HD-Zip-derived START domain. Embedding the START domain within a synthetic transcription factor in yeast, we found that several mammalian START domains from StAR, MLN64 and PCTP stimulated transcription factor activity, as did START domains from two Arabidopsis HD-Zip transcription factors. Mutation of ligandbinding residues within StAR START reduced this activity, consistent with the yeast assay monitoring ligand binding. The D182L missense mutation in StAR START was shown to affect GL2 transcription factor activity in maintainance of the leaf trichome cell fate. Analysis of in vivo protein-metabolite interactions by mass spectrometry provided direct evidence for analogous lipid-binding activity in mammalian and plant START domains in the yeast system. Structural modeling predicted similar sized ligand-binding cavities of a subset of plant START domains in comparison to mammalian counterparts. Conclusions The START domain is required for transcription factor activity in HD-Zip proteins from plants, although it is not strictly necessary for the protein's nuclear localization. START domains from both mammals and plants are modular in that they can bind lipid ligands to regulate transcription factor function in a yeast system. The data provide evidence for an evolutionarily conserved mechanism by which lipid metabolites can orchestrate transcription. We propose a model in which the START domain is used by both plants and mammals to regulate transcription factor activity. [ABSTRACT FROM AUTHOR]
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- 2014
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37. IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.
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Moynihan KD, Kumar MP, Sultan H, Pappas DC, Park T, Chin SM, Bessette P, Lan RY, Nguyen HC, Mathewson ND, Ni I, Chen W, Lee Y, Liao-Chan S, Chen J, Schumacher TNM, Schreiber RD, Yeung YA, and Djuretic IM
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- Animals, Mice, Humans, Cell Line, Tumor, Xenograft Model Antitumor Assays, Female, Neoplasms immunology, Neoplasms drug therapy, CD8-Positive T-Lymphocytes immunology, Interleukin-2 pharmacology
- Abstract
IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rβγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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38. CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.
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Gupta M, Azumaya CM, Moritz M, Pourmal S, Diallo A, Merz GE, Jang G, Bouhaddou M, Fossati A, Brilot AF, Diwanji D, Hernandez E, Herrera N, Kratochvil HT, Lam VL, Li F, Li Y, Nguyen HC, Nowotny C, Owens TW, Peters JK, Rizo AN, Schulze-Gahmen U, Smith AM, Young ID, Yu Z, Asarnow D, Billesbølle C, Campbell MG, Chen J, Chen KH, Chio US, Dickinson MS, Doan L, Jin M, Kim K, Li J, Li YL, Linossi E, Liu Y, Lo M, Lopez J, Lopez KE, Mancino A, Moss FR 3rd, Paul MD, Pawar KI, Pelin A, Pospiech TH Jr, Puchades C, Remesh SG, Safari M, Schaefer K, Sun M, Tabios MC, Thwin AC, Titus EW, Trenker R, Tse E, Tsui TKM, Wang F, Zhang K, Zhang Y, Zhao J, Zhou F, Zhou Y, Zuliani-Alvarez L, Agard DA, Cheng Y, Fraser JS, Jura N, Kortemme T, Manglik A, Southworth DR, Stroud RM, Swaney DL, Krogan NJ, Frost A, Rosenberg OS, and Verba KA
- Abstract
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.
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- 2021
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39. An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation.
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Schoof M, Faust B, Saunders RA, Sangwan S, Rezelj V, Hoppe N, Boone M, Billesbølle CB, Puchades C, Azumaya CM, Kratochvil HT, Zimanyi M, Deshpande I, Liang J, Dickinson S, Nguyen HC, Chio CM, Merz GE, Thompson MC, Diwanji D, Schaefer K, Anand AA, Dobzinski N, Zha BS, Simoneau CR, Leon K, White KM, Chio US, Gupta M, Jin M, Li F, Liu Y, Zhang K, Bulkley D, Sun M, Smith AM, Rizo AN, Moss F, Brilot AF, Pourmal S, Trenker R, Pospiech T, Gupta S, Barsi-Rhyne B, Belyy V, Barile-Hill AW, Nock S, Liu Y, Krogan NJ, Ralston CY, Swaney DL, García-Sastre A, Ott M, Vignuzzi M, Walter P, and Manglik A
- Abstract
Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century., Competing Interests: Competing Interests M.Schoof, B.Faust, R.A.Saunders, N.Hoppe, P.Walter, and A.Manglik are inventors on a provisional patent describing anti-Spike nanobodies described in this manuscript.
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- 2020
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