5hot

Structural Basis for Inhibitor-Induced Aggregation of HIV-1 Integrase

spinqualitylabelsall models 5hot, resolution 4.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5hot is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 4.4Å Ligands: 2SQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q72498_9HIV1 Publication Abstract from PubMed The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 A resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization. Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.,Gupta K, Turkki V, Sherrill-Mix S, Hwang Y, Eilers G, Taylor L, McDanal C, Wang P, Temelkoff D, Nolte RT, Velthuisen E, Jeffrey J, Van Duyne GD, Bushman FD PLoS Biol. 2016 Dec 9;14(12):e1002584. doi: 10.1371/journal.pbio.1002584., eCollection 2016 Dec. PMID:27935939 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Retroviral integrase 3D structures

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