2I5J

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

Summary for 2I5J

• Entry DOI: 10.2210/pdb2i5j/pdb
• Related PRD ID: PRD_900003
• Descriptor: Reverse transcriptase/ribonuclease H P66 subunit, Reverse transcriptase/ribonuclease H P51 subunit, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: aids, hiv, reverse transcriptase, rt, rnase h inhibitor, rnhi, structure-based drug design, protein-inhibitor complex, drug resistance, transferase
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 2
• Total formula weight: 115398.26

Authors

Himmel, D.M.,Sarafianos, S.G.,Knight, J.L.,Levy, R.M.,Arnold, E. (deposition date: 2006-08-24, release date: 2006-12-05, Last modification date: 2023-08-30)

Primary citation

Himmel, D.M.,Sarafianos, S.G.,Dharmasena, S.,Hossain, M.M.,McCoy-Simandle, K.,Ilina, T.,Clark, A.D.,Knight, J.L.,Julias, J.G.,Clark, P.K.,Krogh-Jespersen, K.,Levy, R.M.,Hughes, S.H.,Parniak, M.A.,Arnold, E.
HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site.
Acs Chem.Biol., 1:702-712, 2006

PubMed Abstract: 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.

PubMed: 17184135
DOI: 10.1021/cb600303y

Experimental method

X-RAY DIFFRACTION (3.15 Å)