2be2

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spinqualitylabelsall models 2be2, resolution 2.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with R221239

Overview

In the treatment of AIDS, the efficacy of all drugs, including, non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses., Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT, mutations that cause resistance to NNRTIs in the clinic. We report X-ray, crystal structures for RT complexed with three different pyridinone, derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A, resolution, respectively. All three ligands exhibit nanomolar or, subnanomolar inhibitory activity against wild-type RT, but varying, activities against drug-resistant mutants. R165481 and R221239 differ from, most NNRTIs in that binding does not involve significant contacts with, Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and, drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These, properties result in part from an iodine atom on the pyridinone ring of, both inhibitors that interacts with the main-chain carbonyl oxygen of, Tyr188. An acrylonitrile substituent on R165481 substantially improves the, activity of the compound against wild-type RT (and several mutants) and, provides a way to generate novel inhibitors that could interact with, conserved elements of HIV-1 RT at the polymerase catalytic site. In, R221239, there is a flexible linker to a furan ring that permits, interactions with Val106, Phe227, and Pro236. These contacts appear to, enhance the inhibitory activity of R221239 against the HIV-1 strains that, carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.

About this Structure

2BE2 is a Protein complex structure of sequences from Human immunodeficiency virus 1 with SUC, MN, R22 and GOL as ligands. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

Reference

Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains., Himmel DM, Das K, Clark AD Jr, Hughes SH, Benjahad A, Oumouch S, Guillemont J, Coupa S, Poncelet A, Csoka I, Meyer C, Andries K, Nguyen CH, Grierson DS, Arnold E, J Med Chem. 2005 Dec 1;48(24):7582-91. PMID:16302798

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