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bioRxiv · 10.1101/2020.10.13.337212

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

Anand, G. S.·Palur, R.·Tulsian, N. K.·Samsudin, F.·Qian, X.·Purushotorman, K.·Yue, G.·McQueen, M. K.·Lescar, J.·Bond, P.·McAry, P. A.
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Abstract

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 [A] away while dampening dynamics of the stalk hinge (central helix and heptad repeat) regions ~ 130 [A] 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 SummarySARS-CoV-2 spike protein binding to receptor ACE2 allosterically enhances furin proteolysis at distal S1/S2 cleavage sites

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Anand, G. S., Palur, R., Tulsian, N. K., Samsudin, F., Qian, X., Purushotorman, K., Yue, G., McQueen, M. K., Lescar, J., Bond, P., McAry, P. A.. 2020-10-16. SARS-CoV-2 S protein ACE2 interaction reveals novel allosteric targets. https://doi.org/10.1101/2020.10.13.337212

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