2ops
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The selection of drug resistant viruses is a major problem in efforts to | + | 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. |
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
| - | Relationship of | + | 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., Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Chan JH, Kleim JP, Stammers DK, J Med Chem. 2007 May 17;50(10):2301-9. Epub 2007 Apr 19. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17441703 17441703] |
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: RNA-directed DNA polymerase]] | [[Category: RNA-directed DNA polymerase]] | ||
| - | [[Category: Chamberlain, P | + | [[Category: Chamberlain, P P.]] |
| - | [[Category: Chan, J | + | [[Category: Chan, J H.]] |
[[Category: Kleim, J.]] | [[Category: Kleim, J.]] | ||
| - | [[Category: Nichols, C | + | [[Category: Nichols, C E.]] |
[[Category: Ren, J.]] | [[Category: Ren, J.]] | ||
| - | [[Category: Short, S | + | [[Category: Short, S A.]] |
| - | [[Category: Stammers, D | + | [[Category: Stammers, D K.]] |
| - | [[Category: Weaver, K | + | [[Category: Weaver, K L.]] |
[[Category: HBQ]] | [[Category: HBQ]] | ||
[[Category: PO4]] | [[Category: PO4]] | ||
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[[Category: nnrti]] | [[Category: nnrti]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:21:20 2008'' |
Revision as of 16:21, 21 February 2008
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Crystal Structure of Y188C Mutant HIV-1 Reverse Transcriptase in Complex with GW420867X.
Overview
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.
About this Structure
2OPS is a Protein complex structure of sequences from Human immunodeficiency virus 1 with and as ligands. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
Reference
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., Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Chan JH, Kleim JP, Stammers DK, J Med Chem. 2007 May 17;50(10):2301-9. Epub 2007 Apr 19. PMID:17441703
Page seeded by OCA on Thu Feb 21 18:21:20 2008
