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Artikel ; Online: Mapping interactions of calmodulin and neuronal NO synthase by crosslinking and mass spectrometry.

Felker, Dana / Lee, Kanghyun / Pospiech, Thomas H / Morishima, Yoshihiro / Zhang, Haoming / Lau, Miranda / Southworth, Daniel R / Osawa, Yoichi

The Journal of biological chemistry

2023 Band 300, Heft 1, Seite(n) 105464

Abstract: Neuronal nitric oxide synthase (nNOS) is a homodimeric cytochrome P450-like enzyme that catalyzes the conversion of L-arginine to nitric oxide in the presence of NADPH and molecular oxygen. The binding of calmodulin (CaM) to a linker region between the ... ...

Abstract	Neuronal nitric oxide synthase (nNOS) is a homodimeric cytochrome P450-like enzyme that catalyzes the conversion of L-arginine to nitric oxide in the presence of NADPH and molecular oxygen. The binding of calmodulin (CaM) to a linker region between the FAD/FMN-containing reductase domain, and the heme-containing oxygenase domain is needed for electron transfer reactions, reduction of the heme, and NO synthesis. Due to the dynamic nature of the reductase domain and low resolution of available full-length structures, the exact conformation of the CaM-bound active complex during heme reduction is still unresolved. Interestingly, hydrogen-deuterium exchange and mass spectrometry studies revealed interactions of the FMN domain and CaM with the oxygenase domain for iNOS, but not nNOS. This finding prompted us to utilize covalent crosslinking and mass spectrometry to clarify interactions of CaM with nNOS. Specifically, MS-cleavable bifunctional crosslinker disuccinimidyl dibutyric urea was used to identify thirteen unique crosslinks between CaM and nNOS as well as 61 crosslinks within the nNOS. The crosslinks provided evidence for CaM interaction with the oxygenase and reductase domain residues as well as interactions of the FMN domain with the oxygenase dimer. Cryo-EM studies, which gave a high-resolution model of the oxygenase domain, along with crosslink-guided docking provided a model of nNOS that brings the FMN within 15 Å of the heme in support for a more compact conformation than previously observed. These studies also point to the utility of covalent crosslinking and mass spectrometry in capturing transient dynamic conformations that may not be captured by hydrogen-deuterium exchange and mass spectrometry experiments.
Mesh-Begriff(e)	Calmodulin/metabolism ; Heme/metabolism ; Mass Spectrometry ; Nitric Oxide Synthase Type I/metabolism ; Oxygenases/metabolism ; Cross-Linking Reagents/chemistry ; Calcium/chemistry ; Models, Molecular ; Protein Structure, Quaternary ; Protein Binding ; Cryoelectron Microscopy
Chemische Substanzen	Calmodulin ; Heme (42VZT0U6YR) ; Nitric Oxide Synthase Type I (EC 1.14.13.39) ; Oxygenases (EC 1.13.-) ; Cross-Linking Reagents ; Calcium (SY7Q814VUP)
Sprache	Englisch
Erscheinungsdatum	2023-11-16
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105464
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.

Remesh, Soumya G / Merz, Gregory E / Brilot, Axel F / Chio, Un Seng / Rizo, Alexandrea N / Pospiech, Thomas H / Lui, Irene / Laurie, Mathew T / Glasgow, Jeff / Le, Chau Q / Zhang, Yun / Diwanji, Devan / Hernandez, Evelyn / Lopez, Jocelyne / Mehmood, Hevatib / Pawar, Komal Ishwar / Pourmal, Sergei / Smith, Amber M / Zhou, Fengbo /

DeRisi, Joseph / Kortemme, Tanja / Rosenberg, Oren S / Glasgow, Anum / Leung, Kevin K / Wells, James A / Verba, Kliment A

Structure (London, England : 1993)

2023 Band 31, Heft 3, Seite(n) 253–264.e6

Abstract: The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to ... ...

Abstract	The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.
Mesh-Begriff(e)	Humans ; Angiotensin-Converting Enzyme 2 ; COVID-19 ; SARS-CoV-2 ; Antibodies, Monoclonal ; Protein Binding ; Antibodies, Neutralizing
Chemische Substanzen	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Antibodies, Monoclonal ; Antibodies, Neutralizing
Sprache	Englisch
Erscheinungsdatum	2023-02-17
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2023.01.009
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.

Remesh, Soumya G / Merz, Gregory E / Brilot, Axel F / Chio, Un Seng / Rizo, Alexandrea N / Pospiech, Thomas H / Lui, Irene / Laurie, Mathew T / Glasgow, Jeff / Le, Chau Q / Zhang, Yun / Diwanji, Devan / Hernandez, Evelyn / Lopez, Jocelyne / Pawar, Komal Ishwar / Pourmal, Sergei / Smith, Amber M / Zhou, Fengbo / DeRisi, Joseph /

Kortemme, Tanja / Rosenberg, Oren S / Glasgow, Anum / Leung, Kevin K / Wells, James A / Verba, Kliment A

bioRxiv : the preprint server for biology

2022

Abstract: The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to ... ...

Abstract	The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-Spike-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high affinity (0.53 - 4.2nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron- and Delta-pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.
Sprache	Englisch
Erscheinungsdatum	2022-08-10
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2022.08.09.503400
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps

Remesh, Soumya G. / Merz, Gregory E. / Britol, Axel F. / Chio, Un Seng / Rizo, Alexandrea N / Pospiech, Thomas H / Lui, Irene / Laurie, Mathew T / Glasgow, Jeff / Le, Chau Q. / Zhang, Yun / Diwanji, Devan / Hernandez, Evelyn / Lopez, Jocelyne / Pawar, Komal Ishwar / Pourmal, Sergei / Smith, Amber M / Zhou, Fengbo / QBI Coronavirus Research Group Structural Biology Consortium /

DeRisi, Joseph / Kortemme, Tanja / Rosenberg, Oren S / Glasgow, Anum / Leung, Kevin K / Wells, James A / Verba, Kliment A

bioRxiv

Abstract	The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-Spike-RBD and prevent viral entry into host cells (receptor traps). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high affinity (0.53 - 4.2nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron- and Delta- pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2022-08-10
Verlag	Cold Spring Harbor Laboratory
Dokumenttyp	Artikel ; Online
DOI	10.1101/2022.08.09.503400
Datenquelle	COVID19

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

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 / 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 / Verba, Kliment A

Research square

2021

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- ... ...

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.
Sprache	Englisch
Erscheinungsdatum	2021-05-19
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.21203/rs.3.rs-515215/v1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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

bioRxiv : the preprint server for biology

2021

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.
Sprache	Englisch
Erscheinungsdatum	2021-05-11
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2021.05.10.443524
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes

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 / QCRG Structural Biology Consortium / 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 / Verba, Kliment A

bioRxiv

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.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2021-05-12
Verlag	Cold Spring Harbor Laboratory
Dokumenttyp	Artikel ; Online
DOI	10.1101/2021.05.10.443524
Datenquelle	COVID19

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Artikel ; Online: Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

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 / 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 / Hodder, Anthony J / Shun-Shion, Amber S / 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 / Haupt, Robert / 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 / Toth, Rachel / Goodman, Nicola / Keough, Kathleen C / Lind, Abigail L / 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 / Krogan, Nevan J

Science (New York, N.Y.)

2020 Band 370, Heft 6521

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 ...

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.
Mesh-Begriff(e)	COVID-19/metabolism ; Conserved Sequence ; Coronavirus Nucleocapsid Proteins/genetics ; Coronavirus Nucleocapsid Proteins/metabolism ; Cryoelectron Microscopy ; Host Microbial Interactions ; Humans ; Mitochondrial Membrane Transport Proteins/genetics ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Precursor Protein Import Complex Proteins ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Protein Conformation ; Protein Interaction Maps ; Severe acute respiratory syndrome-related coronavirus/metabolism ; SARS-CoV-2/metabolism ; Severe Acute Respiratory Syndrome/metabolism
Chemische Substanzen	Coronavirus Nucleocapsid Proteins ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Precursor Protein Import Complex Proteins ; Phosphoproteins ; TOMM70 protein, human ; nucleocapsid phosphoprotein, SARS-CoV-2
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2020-10-15
Erscheinungsland	United States
Dokumenttyp	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abe9403
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

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 / 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 / Hodder, Anthony J. / Shun-Shion, Amber S. / 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 / Haupt, Robert / 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 / Toth, Rachel / Goodman, Nicola / Keough, Kathleen C. / Lind, Abigail L. / 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 / Krogan, Nevan J.

Science

2020 , Seite(n) eabe9403

Abstract: The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant 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 ... ...

Abstract	The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant 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 MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis 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-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
Schlagwörter	Multidisciplinary ; covid19
Sprache	Englisch
Verlag	American Association for the Advancement of Science (AAAS)
Erscheinungsland	us
Dokumenttyp	Artikel ; Online
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abe9403
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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