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Your search keyword '"Li, Junrui"' showing total 4 results
Start Over Author "Li, Junrui" Topic biodefense
4 results on '"Li, Junrui"'

1. CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes

Author

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

Subjects
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.

Published
2021

2. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2

Author

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

Subjects
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.

Published
2021

3. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Author

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

Subjects
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.

Published
2020

4. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

Author

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

Subjects
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.

Published
2020

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