Abstract
Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target.
Original language | English |
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Article number | e0159622 |
Journal | Journal of Virology |
Volume | 97 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2023 |
Externally published | Yes |
Keywords
- COVID-19
- SARS-CoV
- SARS-CoV-2
- X-ray crystallography
- betacoronaviruses
- convalescent
- cryptic
- epitope
- neutralizing antibodies
- receptor binding domain
- sarbecoviruses
- spike
- structural biology
- variants of concern