PT  - JOURNAL ARTICLE
AU  - Palur Raghuvamsi
AU  - Nikhil Tulsian
AU  - Firdaus Samsudin
AU  - Xinlei Qian
AU  - Kiren Purushotorman
AU  - Gu Yue
AU  - Mary Kozma
AU  - Julien Lescar
AU  - Peter Bond
AU  - Paul MacAry
AU  - Ganesh Anand
TI  - SARS-CoV-2 S protein ACE2 interaction reveals novel allosteric targets
AID  - 10.1101/2020.10.13.337212
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.13.337212
4099  - http://biorxiv.org/content/early/2020/10/16/2020.10.13.337212.short
4100  - http://biorxiv.org/content/early/2020/10/16/2020.10.13.337212.full
AB  - The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells through surface ACE2 receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, we have mapped the S:ACE2 interface and uncovered long-range allosteric propagation of ACE2 binding to sites 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 mechanistic basis for S:ACE2 complex formation, critical for proteolytic processing and viral-host membrane fusion and highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as allosterically exposed cryptic hotspots for potential therapeutic development.One Sentence Summary SARS-CoV-2 spike protein binding to receptor ACE2 allosterically enhances furin proteolysis at distal S1/S2 cleavage sitesHDXMSHydrogen Deuterium Exchange Mass Spectrometry;MDmolecular dynamics,RFURelative Fractional deuterium uptake;RMSFroot mean squared fluctuations;PCAPrincipal Component Analysis;SSpike;UPLCUltra Performance Liquid Chromatography;