3DM2

Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with GW564511.

3DM2 の概要

• エントリーDOI: 10.2210/pdb3dm2/pdb
• 関連するPDBエントリー: 3DLE 3dlg
• 分子名称: Reverse transcriptase/ribonuclease H, p51 RT, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: hiv-1 reverse transcriptase, aids, nnrti, gw564511, drug resistance, k103n mutation, hydrolase, transferase
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1); 詳細
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04585 P04585
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 116700.70

構造登録者

Ren, J.,Chamberlain, P.P.,Stammers, D.K. (登録日: 2008-06-30, 公開日: 2008-08-12, 最終更新日: 2024-10-30)

主引用文献

Ren, J.,Chamberlain, P.P.,Stamp, A.,Short, S.A.,Weaver, K.L.,Romines, K.R.,Hazen, R.,Freeman, A.,Ferris, R.G.,Andrews, C.W.,Boone, L.,Chan, J.H.,Stammers, D.K.
Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors.
J.Med.Chem., 51:5000-5008, 2008

PubMed Abstract: Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.

PubMed: 18665583
DOI: 10.1021/jm8004493

実験手法

X-RAY DIFFRACTION (3.1 Å)