7ld1
Structure of SARS-CoV-2 S protein in complex with Receptor Binding Domain antibody DH1047
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 PubMedSARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-gamma (FcgammaR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcgammaR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies.,Li D, Edwards RJ, Manne K, Martinez DR, Schafer A, Alam SM, Wiehe K, Lu X, Parks R, Sutherland LL, Oguin TH 3rd, McDanal C, Perez LG, Mansouri K, Gobeil SMC, Janowska K, Stalls V, Kopp M, Cai F, Lee E, Foulger A, Hernandez GE, Sanzone A, Tilahun K, Jiang C, Tse LV, Bock KW, Minai M, Nagata BM, Cronin K, Gee-Lai V, Deyton M, Barr M, Von Holle T, Macintyre AN, Stover E, Feldman J, Hauser BM, Caradonna TM, Scobey TD, Rountree W, Wang Y, Moody MA, Cain DW, DeMarco CT, Denny TN, Woods CW, Petzold EW, Schmidt AG, Teng IT, Zhou T, Kwong PD, Mascola JR, Graham BS, Moore IN, Seder R, Andersen H, Lewis MG, Montefiori DC, Sempowski GD, Baric RS, Acharya P, Haynes BF, Saunders KO Cell. 2021 Aug 5;184(16):4203-4219.e32. doi: 10.1016/j.cell.2021.06.021. Epub , 2021 Jun 18. PMID:34242577[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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