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...

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Vydáno v:	eLife Ročník 10
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England eLife Science Publications, Ltd 08.02.2021 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Témata:	ACE2 Allosteric properties Allosteric Site allostery Amino Acid Sequence Angiotensin Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 - chemistry Angiotensin-Converting Enzyme 2 - metabolism Binding Sites Biochemistry and Chemical Biology Coronaviruses COVID-19 COVID-19 - metabolism COVID-19 - virology Enzymes HDXMS Health aspects Humans Hydrogen-deuterium exchange Mass spectrometry Mass Spectrometry - methods Mass spectroscopy Membrane fusion Molecular dynamics Molecular Dynamics Simulation Peptides Peptidyl-dipeptidase A Proteases Protein Binding Protein Processing, Post-Translational Proteinase Proteins Proteolysis Receptors, Virus - chemistry Receptors, Virus - metabolism SARS-CoV-2 SARS-CoV-2 - metabolism SARS-CoV-2 - physiology Severe acute respiratory syndrome coronavirus 2 Simulation spike Spike Glycoprotein, Coronavirus - chemistry Spike Glycoprotein, Coronavirus - metabolism Structural Biology and Molecular Biophysics Virus Internalization virus-host interactions Viruses ACE2 SARS-CoV-2 virus-host interactions HDXMS chemical biology biochemistry structural biology molecular biophysics allostery spike
ISSN:	2050-084X, 2050-084X
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.63646