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SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets
The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen–deuterium exchange mass spectrometry and molecular dynamics simulations...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932696/ https://www.ncbi.nlm.nih.gov/pubmed/33554856 http://dx.doi.org/10.7554/eLife.63646 |
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author | Raghuvamsi, Palur V Tulsian, Nikhil K Samsudin, Firdaus Qian, Xinlei Purushotorman, Kiren Yue, Gu Kozma, Mary M Hwa, Wong Y Lescar, Julien Bond, Peter J MacAry, Paul A Anand, Ganesh S |
author_facet | Raghuvamsi, Palur V Tulsian, Nikhil K Samsudin, Firdaus Qian, Xinlei Purushotorman, Kiren Yue, Gu Kozma, Mary M Hwa, Wong Y Lescar, Julien Bond, Peter J MacAry, Paul A Anand, Ganesh S |
author_sort | Raghuvamsi, Palur V |
collection | PubMed |
description | The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen–deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat [HR]) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the prefusion state. Our findings provide a dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral–host membrane fusion. Thus, protease docking sites flanking the S1/S2 cleavage site represent alternate allosteric hotspot targets for potential therapeutic development. |
format | Online Article Text |
id | pubmed-7932696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-79326962021-03-08 SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets Raghuvamsi, Palur V Tulsian, Nikhil K Samsudin, Firdaus Qian, Xinlei Purushotorman, Kiren Yue, Gu Kozma, Mary M Hwa, Wong Y Lescar, Julien Bond, Peter J MacAry, Paul A Anand, Ganesh S eLife Biochemistry and Chemical Biology The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen–deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat [HR]) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the prefusion state. Our findings provide a dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral–host membrane fusion. Thus, protease docking sites flanking the S1/S2 cleavage site represent alternate allosteric hotspot targets for potential therapeutic development. eLife Sciences Publications, Ltd 2021-02-08 /pmc/articles/PMC7932696/ /pubmed/33554856 http://dx.doi.org/10.7554/eLife.63646 Text en © 2021, Raghuvamsi et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Raghuvamsi, Palur V Tulsian, Nikhil K Samsudin, Firdaus Qian, Xinlei Purushotorman, Kiren Yue, Gu Kozma, Mary M Hwa, Wong Y Lescar, Julien Bond, Peter J MacAry, Paul A Anand, Ganesh S SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title | SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title_full | SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title_fullStr | SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title_full_unstemmed | SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title_short | SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets |
title_sort | sars-cov-2 s protein:ace2 interaction reveals novel allosteric targets |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932696/ https://www.ncbi.nlm.nih.gov/pubmed/33554856 http://dx.doi.org/10.7554/eLife.63646 |
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