8tm1 | pdb_00008tm1

Antibody N3-1 bound to RBDs in the up and down conformations

spinqualitylabelsall models 8tm1, resolution 2.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tm1 is a 4 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus 2. This structure supersedes the now removed PDB entry 7six. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.79Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Publication Abstract from PubMed The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has provided unprecedented insight into mutations enabling immune escape. Understanding how these mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryogenic electron microscopy revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs. SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode.,Goike J, Hsieh CL, Horton AP, Gardner EC, Zhou L, Bartzoka F, Wang N, Javanmardi K, Herbert A, Abbassi S, Xie X, Xia H, Shi PY, Renberg R, Segall-Shapiro TH, Terrace CI, Wu W, Shroff R, Byrom M, Ellington AD, Marcotte EM, Musser JM, Kuchipudi SV, Kapur V, Georgiou G, Weaver SC, Dye JM, Boutz DR, McLellan JS, Gollihar JD Commun Biol. 2023 Dec 11;6(1):1250. doi: 10.1038/s42003-023-05649-6. PMID:38082099 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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