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

• Published in: Nature communications Vol. 15; no. 1; pp. 8574 - 14
• Main Authors: Yajima, Hisano, Anraku, Yuki, Kaku, Yu, Kimura, Kanako Terakado, Plianchaisuk, Arnon, Okumura, Kaho, Nakada-Nakura, Yoshiko, Atarashi, Yusuke, Hemmi, Takuya, Kuroda, Daisuke, Takahashi, Yoshimasa, Kita, Shunsuke, Sasaki, Jiei, Sumita, Hiromi, Ito, Jumpei, Maenaka, Katsumi, Sato, Kei, Hashiguchi, Takao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 147/28; 631/326/596/2148; 631/326/596/4130; 631/535/1258/1259; 9/10; ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies; Antibodies, Neutralizing - immunology; Binding; Binding Sites; COVID-19; COVID-19 - metabolism; COVID-19 - virology; Glycan; Humanities and Social Sciences; Humans; Infectivity; Models, Molecular; multidisciplinary; Mutation; Neutralization; Neutralizing; Pandemics; Protein Binding; Protein Conformation; Protein Domains; Protein structure; Proteins; Receptors; SARS-CoV-2 - chemistry; SARS-CoV-2 - metabolism; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52808-2

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. JN.1 lineage is a globally dominant variant of SARS-CoV-2. Here, the authors examine structural insights into the BA.2.86 and JN.1 spike dynamics to help understand the mechanisms underlying SARS-CoV-2 infection and its neutralizing-antibody evasion.