9au2 | pdb_00009au2
VIR-7229 Fab fragment bound the BA.2.86 spike trimer (global refinement)
Structural highlights
FunctionSPIKE_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][1] [2] [3] 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 PubMedSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine. A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification.,Rosen LE, Tortorici MA, De Marco A, Pinto D, Foreman WB, Taylor AL, Park YJ, Bohan D, Rietz T, Errico JM, Hauser K, Dang HV, Chartron JW, Giurdanella M, Cusumano G, Saliba C, Zatta F, Sprouse KR, Addetia A, Zepeda SK, Brown J, Lee J, Dellota E Jr, Rajesh A, Noack J, Tao Q, DaCosta Y, Tsu B, Acosta R, Subramanian S, de Melo GD, Kergoat L, Zhang I, Liu Z, Guarino B, Schmid MA, Schnell G, Miller JL, Lempp FA, Czudnochowski N, Cameroni E, Whelan SPJ, Bourhy H, Purcell LA, Benigni F, di Iulio J, Pizzuto MS, Lanzavecchia A, Telenti A, Snell G, Corti D, Veesler D, Starr TN Cell. 2024 Oct 4:S0092-8674(24)01084-5. doi: 10.1016/j.cell.2024.09.026. PMID:39383863[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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