3bgr | pdb_00003bgr

Crystal structure of K103N/Y181C mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (Rilpivirine), a non-nucleoside RT inhibitor

File:3bgr.jpg

spinqualitylabelsall models 3bgr, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D

Overview

TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase, inhibitor (NNRTI) that is highly effective in treating wild-type and, drug-resistant HIV-1 infections in clinical trials at relatively low doses, ( approximately 25-75 mg/day). We have determined the structure of, wild-type HIV-1 RT complexed with TMC278 at 1.8 A resolution, using an RT, crystal form engineered by systematic RT mutagenesis. This high-resolution, structure reveals that the cyanovinyl group of TMC278 is positioned in a, hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic, acid-binding cleft. The crystal structures of TMC278 in complexes with the, double mutant K103N/Y181C (2.1 A) and L100I/K103N HIV-1 RTs (2.9 A), demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C, RT/TMC278 structure, loss of the aromatic ring interaction caused by the, Y181C mutation is counterbalanced by interactions between the cyanovinyl, group of TMC278 and the aromatic side chain of Y183, which is facilitated, by an approximately 1.5 A shift of the conserved Y(183)MDD motif. In the, L100I/K103N RT/TMC278 structure, the binding mode of TMC278 is, significantly altered so that the drug conforms to changes in the binding, pocket primarily caused by the L100I mutation. The flexible binding pocket, acts as a molecular "shrink wrap" that makes a shape complementary to the, optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The, crystal structures provide a better understanding of how the flexibility, of an inhibitor can compensate for drug-resistance mutations.

About this Structure

3BGR is a Protein complex structure of sequences from Human immunodeficiency virus 1 with T27 and EDO as ligands. Known structural/functional Sites: AC1 and AC2. Full crystallographic information is available from OCA.

Reference

High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations., Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71. Epub 2008 Jan 29. PMID:18230722

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