2i5j

File:2i5j.gif

spinqualitylabelsall models 2i5j, resolution 3.150Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with DHBNH, an RNASE H inhibitor

Overview

The rapid emergence of drug-resistant variants of human immunodeficiency, virus, type 1 (HIV-1), has limited the efficacy of anti-acquired immune, deficiency syndrome (AIDS) treatments, and new lead compounds that target, novel binding sites are needed. We have determined the 3.15 A resolution, crystal structure of HIV-1 reverse transcriptase (RT) complexed with, dihydroxy benzoyl naphthyl hydrazone (DHBNH), an HIV-1 RT RNase H (RNH), inhibitor (RNHI). DHBNH is effective against a variety of drug-resistant, HIV-1 RT mutants. While DHBNH has little effect on most aspects of, RT-catalyzed DNA synthesis, at relatively high concentrations it does, inhibit the initiation of RNA-primed DNA synthesis. Although primarily an, RNHI, DHBNH binds >50 A away from the RNH active site, at a novel site, near both the polymerase active site and the non-nucleoside RT inhibitor, (NNRTI) binding pocket. When DHBNH binds, both Tyr181 and Tyr188 remain in, the conformations seen in unliganded HIV-1 RT. DHBNH interacts with, conserved residues (Asp186, Trp229) and has substantial interactions with, the backbones of several less well-conserved residues. On the basis of, this structure, we designed substituted DHBNH derivatives that interact, with the NNRTI-binding pocket. These compounds inhibit both the polymerase, and RNH activities of RT.

About this Structure

2I5J is a Protein complex structure of sequences from Human immunodeficiency virus 1 with GLC, SUC, MG and K05 as ligands. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

Reference

HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site., Himmel DM, Sarafianos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, Clark AD Jr, Knight JL, Julias JG, Clark PK, Krogh-Jespersen K, Levy RM, Hughes SH, Parniak MA, Arnold E, ACS Chem Biol. 2006 Dec 20;1(11):702-12. PMID:17184135

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