2ZE2

Crystal structure of L100I/K103N mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (rilpivirine), a non-nucleoside RT inhibitor

Summary for 2ZE2

• Entry DOI: 10.2210/pdb2ze2/pdb
• Related: 1S6Q 1SV5 2IC3 2ZD1 3BGR
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile (3 entities in total)
• Functional Keywords: p51/p66, hetero dimer, nnrti, nonnucleoside inhibitor, aids, hiv, r278474, rilpivirine, diarylpyrimidine, dapy, dna recombination, rna-directed dna polymerase, dna polymerase, endonuclease, hydrolase, multifunctional enzyme, transferase
• Biological source: Human immunodeficiency virus 1; More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 114380.07

Authors

Das, K.,Bauman, J.D.,Clark Jr., A.D.,Shatkin, A.J.,Arnold, E. (deposition date: 2007-12-05, release date: 2008-02-12, Last modification date: 2023-11-01)

Primary citation

Das, K.,Bauman, J.D.,Clark Jr., A.D.,Frenkel, Y.V.,Lewi, P.J.,Shatkin, A.J.,Hughes, S.H.,Arnold, E.
High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations.
Proc.Natl.Acad.Sci.Usa, 105:1466-1471, 2008

PubMed Abstract: 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.

PubMed: 18230722
DOI: 10.1073/pnas.0711209105

Experimental method

X-RAY DIFFRACTION (2.9 Å)