Structural basis for SARS-CoV-2 Delta variant recognition of ACE2 receptor and broadly neutralizing antibodies

Yifan Wang, Caixuan Liu, Chao Zhang, Yanxing Wang, Qin Hong, Shiqi Xu, Zuyang Li, Yong Yang, Zhong Huang () and Yao Cong ()
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Yifan Wang: Chinese Academy of Sciences
Caixuan Liu: Chinese Academy of Sciences
Chao Zhang: University of Chinese Academy of Sciences
Yanxing Wang: Chinese Academy of Sciences
Qin Hong: Chinese Academy of Sciences
Shiqi Xu: University of Chinese Academy of Sciences
Zuyang Li: Chinese Academy of Sciences
Yong Yang: University of Chinese Academy of Sciences
Zhong Huang: University of Chinese Academy of Sciences
Yao Cong: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract The SARS-CoV-2 Delta variant is currently the dominant circulating strain in the world. Uncovering the structural basis of the enhanced transmission and altered immune sensitivity of Delta is particularly important. Here we present cryo-EM structures revealing two conformational states of Delta spike and S/ACE2 complex in four states. Our cryo-EM analysis suggests that RBD destabilizations lead to population shift towards the more RBD-up and S1 destabilized fusion-prone state, beneficial for engagement with ACE2 and shedding of S1. Noteworthy, we find the Delta T478K substitution plays a vital role in stabilizing and reshaping the RBM loop473-490, enhancing interaction with ACE2. Collectively, increased propensity for more RBD-up states and the affinity-enhancing T478K substitution together contribute to increased ACE2 binding, providing structural basis of rapid spread of Delta. Moreover, we identify a previously generated MAb 8D3 as a cross-variant broadly neutralizing antibody and reveal that 8D3 binding induces a large K478 side-chain orientation change, suggesting 8D3 may use an “induced-fit” mechanism to tolerate Delta T478K mutation. We also find that all five RBD-targeting MAbs tested remain effective on Delta, suggesting that Delta well preserves the neutralizing antigenic landscape in RBD. Our findings shed new lights on the pathogenicity and antibody neutralization of Delta.

Date: 2022
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DOI: 10.1038/s41467-022-28528-w

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