8smi
From Proteopedia
Crystal structure of antibody WRAIR-2123 in complex with SARS-CoV-2 receptor binding domain
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 PubMedGiven the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 A and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies. Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain.,Sankhala RS, Dussupt V, Chen WH, Bai H, Martinez EJ, Jensen JL, Rees PA, Hajduczki A, Chang WC, Choe M, Yan L, Sterling SL, Swafford I, Kuklis C, Soman S, King J, Corbitt C, Zemil M, Peterson CE, Mendez-Rivera L, Townsley SM, Donofrio GC, Lal KG, Tran U, Green EC, Smith C, de Val N, Laing ED, Broder CC, Currier JR, Gromowski GD, Wieczorek L, Rolland M, Paquin-Proulx D, van Dyk D, Britton Z, Rajan S, Loo YM, McTamney PM, Esser MT, Polonis VR, Michael NL, Krebs SJ, Modjarrad K, Joyce MG Structure. 2024 Feb 1;32(2):131-147.e7. doi: 10.1016/j.str.2023.11.015. Epub 2023 , Dec 28. PMID:38157856[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found References
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