tetano
Editor, Senior Moderator
Cell Host Microbe
. 2020 Jun 19;S1931-3128(20)30351-6.
doi: 10.1016/j.chom.2020.06.010. Online ahead of print.
Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike
Jiandong Huo[SUP] 1 [/SUP], Yuguang Zhao[SUP] 2 [/SUP], Jingshan Ren[SUP] 3 [/SUP], Daming Zhou[SUP] 2 [/SUP], Helen M E Duyvesteyn[SUP] 2 [/SUP], Helen M Ginn[SUP] 4 [/SUP], Loic Carrique[SUP] 2 [/SUP], Tomas Malinauskas[SUP] 2 [/SUP], Reinis R Ruza[SUP] 2 [/SUP], Pranav N M Shah[SUP] 2 [/SUP], Tiong Kit Tan[SUP] 5 [/SUP], Pramila Rijal[SUP] 6 [/SUP], Naomi Coombes[SUP] 7 [/SUP], Kevin R Bewley[SUP] 7 [/SUP], Julia A Tree[SUP] 7 [/SUP], Julika Radecke[SUP] 4 [/SUP], Neil G Paterson[SUP] 4 [/SUP], Piyasa Supasa[SUP] 8 [/SUP], Juthathip Mongkolsapaya[SUP] 9 [/SUP], Gavin R Screaton[SUP] 8 [/SUP], Miles Carroll[SUP] 10 [/SUP], Alain Townsend[SUP] 6 [/SUP], Elizabeth E Fry[SUP] 2 [/SUP], Raymond J Owens[SUP] 1 [/SUP], David I Stuart[SUP] 11 [/SUP]
Affiliations
Abstract
There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 ? of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.
Keywords: CR3022; SARS-CoV-2; X-ray crystallography; antibody; cryo-electron microscopy; epitope; neutralization; receptor binding domain; spike; therapeutic.
. 2020 Jun 19;S1931-3128(20)30351-6.
doi: 10.1016/j.chom.2020.06.010. Online ahead of print.
Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike
Jiandong Huo[SUP] 1 [/SUP], Yuguang Zhao[SUP] 2 [/SUP], Jingshan Ren[SUP] 3 [/SUP], Daming Zhou[SUP] 2 [/SUP], Helen M E Duyvesteyn[SUP] 2 [/SUP], Helen M Ginn[SUP] 4 [/SUP], Loic Carrique[SUP] 2 [/SUP], Tomas Malinauskas[SUP] 2 [/SUP], Reinis R Ruza[SUP] 2 [/SUP], Pranav N M Shah[SUP] 2 [/SUP], Tiong Kit Tan[SUP] 5 [/SUP], Pramila Rijal[SUP] 6 [/SUP], Naomi Coombes[SUP] 7 [/SUP], Kevin R Bewley[SUP] 7 [/SUP], Julia A Tree[SUP] 7 [/SUP], Julika Radecke[SUP] 4 [/SUP], Neil G Paterson[SUP] 4 [/SUP], Piyasa Supasa[SUP] 8 [/SUP], Juthathip Mongkolsapaya[SUP] 9 [/SUP], Gavin R Screaton[SUP] 8 [/SUP], Miles Carroll[SUP] 10 [/SUP], Alain Townsend[SUP] 6 [/SUP], Elizabeth E Fry[SUP] 2 [/SUP], Raymond J Owens[SUP] 1 [/SUP], David I Stuart[SUP] 11 [/SUP]
Affiliations
- PMID: 32585135
- DOI: 10.1016/j.chom.2020.06.010
Abstract
There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 ? of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.
Keywords: CR3022; SARS-CoV-2; X-ray crystallography; antibody; cryo-electron microscopy; epitope; neutralization; receptor binding domain; spike; therapeutic.