7txd
From Proteopedia
Cryo-EM structure of BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) and broadly neutralizing darpin bnD.9
Structural highlights
FunctionQ2N0S6_9HIV1 The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).[SAAS:SAAS000328_004_240990] Publication Abstract from PubMedThe third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic alpha-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'alphaV3C'. The bnD contact surface on alphaV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of alphaV3C, highlighting the potential of alphaV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1. Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.,Glogl M, Friedrich N, Cerutti G, Lemmin T, Kwon YD, Gorman J, Maliqi L, Mittl PRE, Hesselman MC, Schmidt D, Weber J, Foulkes C, Dingens AS, Bylund T, Olia AS, Verardi R, Reinberg T, Baumann NS, Rusert P, Dreier B, Shapiro L, Kwong PD, Pluckthun A, Trkola A Nat Struct Mol Biol. 2023 Sep;30(9):1323-1336. doi: 10.1038/s41594-023-01062-z. , Epub 2023 Aug 21. PMID:37605043[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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