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Structure
. 2023 Dec 16:S0969-2126(23)00440-9.
doi: 10.1016/j.str.2023.11.015. Online ahead of print. Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain
Rajeshwer S Sankhala 1 , Vincent Dussupt 2 , Wei-**** Chen 1 , Hongjun Bai 2 , Elizabeth J Martinez 1 , Jaime L Jensen 1 , Phyllis A Rees 1 , Agnes Hajduczki 1 , William C Chang 1 , Misook Choe 1 , Lianying Yan 3 , Spencer L Sterling 3 , Isabella Swafford 4 , Caitlin Kuklis 5 , Sandrine Soman 5 , Jocelyn King 5 , Courtney Corbitt 5 , Michelle Zemil 4 , Caroline E Peterson 1 , Letzibeth Mendez-Rivera 4 , Samantha M Townsley 4 , Gina C Donofrio 4 , Kerri G Lal 2 , Ursula Tran 4 , Ethan C Green 3 , Clayton Smith 6 , Natalia de Val 6 , Eric D Laing 3 , Christopher C Broder 3 , Jeffrey R Currier 5 , Gregory D Gromowski 5 , Lindsay Wieczorek 4 , Morgane Rolland 2 , Dominic Paquin-Proulx 4 , Dewald van Dyk 7 , Zachary Britton 7 , Saravanan Rajan 7 , Yueh Ming Loo 8 , Patrick M McTamney 8 , Mark T Esser 8 , Victoria R Polonis 9 , Nelson L Michael 10 , Shelly J Krebs 11 , Kayvon Modjarrad 12 , M Gordon Joyce 13
Affiliations
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.
. 2023 Dec 16:S0969-2126(23)00440-9.
doi: 10.1016/j.str.2023.11.015. Online ahead of print. Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain
Rajeshwer S Sankhala 1 , Vincent Dussupt 2 , Wei-**** Chen 1 , Hongjun Bai 2 , Elizabeth J Martinez 1 , Jaime L Jensen 1 , Phyllis A Rees 1 , Agnes Hajduczki 1 , William C Chang 1 , Misook Choe 1 , Lianying Yan 3 , Spencer L Sterling 3 , Isabella Swafford 4 , Caitlin Kuklis 5 , Sandrine Soman 5 , Jocelyn King 5 , Courtney Corbitt 5 , Michelle Zemil 4 , Caroline E Peterson 1 , Letzibeth Mendez-Rivera 4 , Samantha M Townsley 4 , Gina C Donofrio 4 , Kerri G Lal 2 , Ursula Tran 4 , Ethan C Green 3 , Clayton Smith 6 , Natalia de Val 6 , Eric D Laing 3 , Christopher C Broder 3 , Jeffrey R Currier 5 , Gregory D Gromowski 5 , Lindsay Wieczorek 4 , Morgane Rolland 2 , Dominic Paquin-Proulx 4 , Dewald van Dyk 7 , Zachary Britton 7 , Saravanan Rajan 7 , Yueh Ming Loo 8 , Patrick M McTamney 8 , Mark T Esser 8 , Victoria R Polonis 9 , Nelson L Michael 10 , Shelly J Krebs 11 , Kayvon Modjarrad 12 , M Gordon Joyce 13
Affiliations
- PMID: 38157856
- DOI: 10.1016/j.str.2023.11.015
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.