Please use this identifier to cite or link to this item: https://doi.org/10.7554/eLife.63646
Title: SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets
Authors: 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 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
CORONAVIRUS SPIKE GLYCOPROTEIN
RECEPTOR-BINDING
GOLGI-COMPLEX
DYNAMICS
ACE2
SIMULATIONS
DOMAIN
Issue Date: 8-Feb-2021
Publisher: ELIFE SCIENCES PUBLICATIONS LTD
Citation: 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 (2021-02-08). SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets. ELIFE 10. ScholarBank@NUS Repository. https://doi.org/10.7554/eLife.63646
Abstract: The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface 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) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the pre-fusion 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. Our findings highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as alternate allosteric hotspot targets for potential therapeutic development.
Source Title: ELIFE
URI: https://scholarbank.nus.edu.sg/handle/10635/191971
ISSN: 2050084X
2050084X
DOI: 10.7554/eLife.63646
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