biostudies-literatureYajima HMEXT | Japan Society for the Promotion of ScienceMEXT | Japan Society for the Promotion of Science (JSPS)Japan Agency for Medical Research and DevelopmentMEXT | JST | Core Research for Evolutional Science and TechnologyMEXT | JST | Core Research for Evolutional Science and Technology (CREST)Japan Agency for Medical Research and Development (AMED)8574https://www.ebi.ac.uk/biostudies/studies/S-EPMC11458767biostudies-literatureUnknown15(1)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-linkedNature communicationsStructural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1.PMC11458767JP24jf0126002JPMJCR20H8JP20ae0101047JPJSCCA20240006JP223fa627009Nishiuchi TGuo ZOgawa EPlianchaisuk AAsakura HIrie TNasser HHorinaka KKida IUriu KTsujino SDeguchi SSadamas KKaku YMohri HIida KYoshimura RIida MYoshimura KKita SOhari YZahradnik JKosugi YKuroda DSaito AGenotype to Phenotype Japan (G2P-Japan) ConsortiumSasaki JLytras SFukuhara TOsujo RShishido KTsuda MMotozono CSasaki-Tabata KTakayama KNao NTanaka SMatsuno KHashimoto RKosaka AMaenaka KOkumura KAndrikopoulos PFujita SKonar AYoshida INishumura LAnraku YMisawa NAtarashi YSato KOhsumi NFukuda THemmi TWang LStrange APYasuda KIto JIto HKimura KTFerdous ZChiba MLeong SToyoda MPadilla-Blanco MKawano MLi JMugita YChen LSakamoto AUeno TIkeda TLi WNakajima YNakata YFutatsusako HM Tolentino JEMatsubara NHinay AASuzuki RYajima HSuzuki SMimura YSuzuki TShimizu RYo MSSumita HMizuma KOda YTakahashi YSawa HNakada-Nakura YNagashima MTakahashi OJonathan MTamura TWatanabe YKawakubo SUsui KBegum MSTMSuganami MNakagawa SYasuhara NPan LKawabata RHashiguchi TSaikruang WfalseStructural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1.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-linked2024-01-01T00:00:00Z2024 Oct2026-06-16T03:14:32.038Z2025-04-04T01:54:39.173ZS-EPMC114587673937532610.1038/s41467-024-52808-2