4zmj | pdb_00004zmj
Crystal Structure of Ligand-Free BG505 SOSIP.664 HIV-1 Env Trimer
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 PubMedAs the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens. Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env.,Do Kwon Y, Pancera M, Acharya P, Georgiev IS, Crooks ET, Gorman J, Joyce MG, Guttman M, Ma X, Narpala S, Soto C, Terry DS, Yang Y, Zhou T, Ahlsen G, Bailer RT, Chambers M, Chuang GY, Doria-Rose NA, Druz A, Hallen MA, Harned A, Kirys T, Louder MK, O'Dell S, Ofek G, Osawa K, Prabhakaran M, Sastry M, Stewart-Jones GB, Stuckey J, Thomas PV, Tittley T, Williams C, Zhang B, Zhao H, Zhou Z, Donald BR, Lee LK, Zolla-Pazner S, Baxa U, Schon A, Freire E, Shapiro L, Lee KK, Arthos J, Munro JB, Blanchard SC, Mothes W, Binley JM, McDermott AB, Mascola JR, Kwong PD Nat Struct Mol Biol. 2015 Jul;22(7):522-31. doi: 10.1038/nsmb.3051. Epub 2015 Jun, 22. PMID:26098315[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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