Structural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1

Hisano Yajima, Yuki Anraku, Yu Kaku, Kanako Terakado Kimura, Arnon Plianchaisuk, Kaho Okumura, Yoshiko Nakada-Nakura, Yusuke Atarashi, Takuya Hemmi, Daisuke Kuroda, Yoshimasa Takahashi, Shunsuke Kita, Jiei Sasaki, Hiromi Sumita, Jumpei Ito, Katsumi Maenaka, Kei Sato () and Takao Hashiguchi ()
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Hisano Yajima: Kyoto University
Yuki Anraku: Hokkaido University
Yu Kaku: The University of Tokyo
Kanako Terakado Kimura: Kyoto University
Arnon Plianchaisuk: The University of Tokyo
Kaho Okumura: The University of Tokyo
Yoshiko Nakada-Nakura: Kyoto University
Yusuke Atarashi: Kyoto University
Takuya Hemmi: Kyoto University
Daisuke Kuroda: National Institute of Infectious Diseases; Shinjuku-ku
Yoshimasa Takahashi: National Institute of Infectious Diseases; Shinjuku-ku
Shunsuke Kita: Hokkaido University
Jiei Sasaki: Kyoto University
Hiromi Sumita: Kyoto University
Jumpei Ito: The University of Tokyo
Katsumi Maenaka: Hokkaido University
Kei Sato: The University of Tokyo
Takao Hashiguchi: Kyoto University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.

Date: 2024
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DOI: 10.1038/s41467-024-52808-2

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