7beo
From Proteopedia
Crystal structure of the receptor binding domain of SARS-CoV-2 Spike glycoprotein in a ternary complex with COVOX-253H55L and COVOX-75 Fabs
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 PubMedAntibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC(50) < 0.1 mug/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models. The antigenic anatomy of SARS-CoV-2 receptor binding domain.,Dejnirattisai W, Zhou D, Ginn HM, Duyvesteyn HME, Supasa P, Case JB, Zhao Y, Walter TS, Mentzer AJ, Liu C, Wang B, Paesen GC, Slon-Campos J, Lopez-Camacho C, Kafai NM, Bailey AL, Chen RE, Ying B, Thompson C, Bolton J, Fyfe A, Gupta S, Tan TK, Gilbert-Jaramillo J, James W, Knight M, Carroll MW, Skelly D, Dold C, Peng Y, Levin R, Dong T, Pollard AJ, Knight JC, Klenerman P, Temperton N, Hall DR, Williams MA, Paterson NG, Bertram FKR, Siebert CA, Clare DK, Howe A, Radecke J, Song Y, Townsend AR, Huang KA, Fry EE, Mongkolsapaya J, Diamond MS, Ren J, Stuart DI, Screaton GR Cell. 2021 Apr 15;184(8):2183-2200.e22. doi: 10.1016/j.cell.2021.02.032. Epub , 2021 Feb 18. PMID:33756110[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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