5u7o

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to Small Molecule HIV-1 Entry Inhibitor BMS-626529 in Complex with Human Antibodies PGT122 and 35O22 at 3.8 Angstrom

spinqualitylabelsall models 5u7o, resolution 3.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5u7o is a 6 chain structure with sequence from 9hiv1 and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 83J, BMA, NAG, SO4, MAN Related: 5u7m Gene: env (9HIV1) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [Q2N0S5_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.[RuleBase:RU004292][SAAS:SAAS00139820] 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.[SAAS:SAAS00140087] Publication Abstract from PubMed The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-A resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the beta20-21 hairpin. In both structures, the beta20-21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env. Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529.,Pancera M, Lai YT, Bylund T, Druz A, Narpala S, O'Dell S, Schon A, Bailer RT, Chuang GY, Geng H, Louder MK, Rawi R, Soumana DI, Finzi A, Herschhorn A, Madani N, Sodroski J, Freire E, Langley DR, Mascola JR, McDermott AB, Kwong PD Nat Chem Biol. 2017 Aug 21. doi: 10.1038/nchembio.2460. PMID:28825711 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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