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'''CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINE''' | '''CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINE''' | ||
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[[Category: Stuart, D I.]] | [[Category: Stuart, D I.]] | ||
[[Category: Weaver, K L.]] | [[Category: Weaver, K L.]] | ||
[[Category: | [[Category: Aid]] | ||
[[Category: | [[Category: Drug design]] | ||
[[Category: | [[Category: Drug resistance mutation]] | ||
[[Category: | [[Category: Hiv-1 reverse transcriptase]] | ||
[[Category: | [[Category: Nevirapine]] | ||
[[Category: | [[Category: Non-nucleoside inhibitor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 16:26:24 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 16:26, 2 May 2008
CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINE
OverviewOverview
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.
About this StructureAbout this Structure
1FKP is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase., Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK, Structure. 2000 Oct 15;8(10):1089-94. PMID:11080630 Page seeded by OCA on Fri May 2 16:26:24 2008