PDBsum entry 2opr

Transferase

PDB id: 2opr

Contents

Protein chains

539 a.a.

400 a.a.

Ligands

HBQ

References listed in PDB file

Key reference

• Title: Relationship of potency and resilience to drug resistant mutations for gw420867X revealed by crystal structures of inhibitor complexes for wild-Type, Leu100ile, Lys101glu, And tyr188cys mutant HIV-1 reverse transcriptases.
• Authors: J.Ren, C.E.Nichols, P.P.Chamberlain, K.L.Weaver, S.A.Short, J.H.Chan, J.P.Kleim, D.K.Stammers.
• Ref.: J Med Chem, 2007, 50, 2301-2309. [DOI no: 10.1021/jm061117m]
• PubMed id: 17441703

Abstract

The selection of drug resistant viruses is a major problem in efforts to combat HIV and AIDS, hence, new compounds are required. We report crystal structures of wild-type and mutant HIV-1 RT with bound non-nucleoside (NNRTI) GW420867X, aimed at investigating the basis for its high potency and improved drug resistance profile compared to the first-generation drug nevirapine. GW420867X occupies a smaller volume than many NNRTIs, yet accesses key regions of the binding pocket. GW420867X has few contacts with Tyr188, hence, explaining the small effect of mutating this residue on inhibitor-binding potency. In a mutated NNRTI pocket, GW420867X either remains in a similar position compared to wild-type (RT(Leu100Ile) and RT(Tyr188Cys)) or rearranges within the pocket (RT(Lys101Glu)). For RT(Leu100Ile), GW420867X does not shift position, in spite of forming different side-chain contacts. The small bulk of GW420867X allows adaptation to a mutated NNRTI binding site by repositioning or readjustment of side-chain contacts with only small reductions in binding affinity.