Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Rajeshwer S. Sankhala, Vincent Dussupt, Wei Hung Chen, Hongjun Bai, Elizabeth J. Martinez, Jaime L. Jensen, Phyllis A. Rees, Agnes Hajduczki, William C. Chang, Misook Choe, Lianying Yan, Spencer L. Sterling, Isabella Swafford, Caitlin Kuklis, Sandrine Soman, Jocelyn King, Courtney Corbitt, Michelle Zemil, Caroline E. Peterson, Letzibeth Mendez-RiveraSamantha M. Townsley, Gina C. Donofrio, Kerri G. Lal, Ursula Tran, Ethan C. Green, Clayton Smith, Natalia de Val, Eric D. Laing, Christopher C. Broder, Jeffrey R. Currier, Gregory D. Gromowski, Lindsay Wieczorek, Morgane Rolland, Dominic Paquin-Proulx, Dewald van Dyk, Zachary Britton, Saravanan Rajan, Yueh Ming Loo, Patrick M. McTamney, Mark T. Esser, Victoria R. Polonis, Nelson L. Michael, Shelly J. Krebs*, Kayvon Modjarrad, M. Gordon Joyce*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

Original languageEnglish
Pages (from-to)131-147.e7
JournalStructure
Volume32
Issue number2
DOIs
StatePublished - 1 Feb 2024
Externally publishedYes

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