Journal Article

SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

Kozma, Mary M, Raghuvamsi, Palur V, Qian, Xinlei, Purushotorman, Kiren, Hwa, Wong Y, Lescar, Julien, Bond, Peter J, Samsudin, Firdaus, Tulsian, Nikhil K, Anand, Ganesh S, Yue, Gu, MacAry, Paul A

2021

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 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