4p9h
Crystal structure of 8ANC195 Fab in complex with gp120 of 93TH057 HIV-1 and soluble CD4 D1D2Crystal structure of 8ANC195 Fab in complex with gp120 of 93TH057 HIV-1 and soluble CD4 D1D2
Structural highlights
FunctionCD4_HUMAN Accessory protein for MHC class-II antigen/T-cell receptor interaction. May regulate T-cell activation. Induces the aggregation of lipid rafts. Publication Abstract from PubMedBroadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4-binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield by using a single variable-region CDR loop, 8ANC195 inserted its entire heavy-chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with nonoverlapping epitopes. Antibody 8ANC195 Reveals a Site of Broad Vulnerability on the HIV-1 Envelope Spike.,Scharf L, Scheid JF, Lee JH, West AP Jr, Chen C, Gao H, Gnanapragasam PN, Mares R, Seaman MS, Ward AB, Nussenzweig MC, Bjorkman PJ Cell Rep. 2014 May 8;7(3):785-95. doi: 10.1016/j.celrep.2014.04.001. Epub 2014, Apr 24. PMID:24767986[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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