2OPS

Crystal Structure of Y188C Mutant HIV-1 Reverse Transcriptase in Complex with GW420867X.

Summary for 2OPS

• Entry DOI: 10.2210/pdb2ops/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: hiv-1 reverse transcriptase, aids, nnrti, gw420867x, drug resistance, transferase
• Biological source: HIV-1 M:B_HXB2R; More
• Cellular location: Matrix protein p17: Virion . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04585 P04585
• Total number of polymer chains: 2
• Total formula weight: 113928.31

Authors

Ren, J.,Nichols, C.E.,Chamberlain, P.P.,Weaver, K.L.,Short, S.A.,Chan, J.H.,Kleim, J.,Stammers, D.K. (deposition date: 2007-01-30, release date: 2007-05-22, Last modification date: 2023-12-27)

Primary citation

Ren, J.,Nichols, C.E.,Chamberlain, P.P.,Weaver, K.L.,Short, S.A.,Chan, J.H.,Kleim, J.P.,Stammers, D.K.
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.
J.Med.Chem., 50:2301-2309, 2007

PubMed 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.

PubMed: 17441703
DOI: 10.1021/jm061117m

Experimental method

X-RAY DIFFRACTION (2.3 Å)