4tsx | pdb_00004tsx

HIV-1 Integrase Catalytic Core Domain Mutant Complexed with Allosteric Inhibitor

spinqualitylabelsall models 4tsx, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4tsx is a 1 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 1.94Å Ligands: CAF, LF0, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F2WR39_9HIV1 Publication Abstract from PubMed BackgroundAllosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying the principal binding pocket of its cellular cofactor LEDGF/p75. Consequently, ALLINIs inhibit HIV-1 IN interaction with LEDGF/p75 as well as promote aberrant IN multimerization. Selection of viral strains emerging under the inhibitor pressure has revealed mutations at the IN dimer interface near the inhibitor binding site.ResultsWe have investigated the effects of one of the most prevalent substitutions, H171T IN, selected under increasing pressure of ALLINI BI-D. Virus containing the H171T IN substitution exhibited an ~68-fold resistance to BI-D treatment in infected cells. These results correlated with ~84-fold reduced affinity for BI-D binding to recombinant H171T IN CCD protein compared to its wild type (WT) counterpart. However, the H171T IN substitution only modestly affected IN-LEDGF/p75 binding and allowed HIV-1 containing this substitution to replicate at near WT levels. The x-ray crystal structures of BI-D binding to WT and H171T IN CCD dimers coupled with binding free energy calculations revealed the importance of the N inverted question mark- protonated imidazole group of His171 for hydrogen bonding to the BI-D tert-butoxy ether oxygen and establishing electrostatic interactions with the inhibitor carboxylic acid, whereas these interactions were compromised upon substitution to Thr171.ConclusionsOur findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D and indicate a previously undescribed role of the His171 side chain for binding the inhibitor. The mechanism of H171T resistance reveals the importance of N inverted question mark -protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase.,Slaughter A, Jurado KA, Deng N, Feng L, Kessl JJ, Shkriabai N, Larue RC, Fadel HJ, Patel PA, Jena N, Fuchs JR, Poeschla E, Levy RM, Engelman A, Kvaratskhelia M Retrovirology. 2014 Nov 25;11(1):100. PMID:25421939 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Retroviral integrase 3D structures

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