1BQM

HIV-1 RT/HBY 097

1BQM の概要

• エントリーDOI: 10.2210/pdb1bqm/pdb
• 分子名称: REVERSE TRANSCRIPTASE, (S)-4-ISOPROPOXYCARBONYL-6-METHOXY-3-METHYLTHIOMETHYL-3,4-DIHYDROQUINOXALIN-2(1H)-THIONE (3 entities in total)
• 機能のキーワード: nucleotidyltransferase, aids, rna-directed dna polymerase, hiv-1 rt/hby 097, drug-resistant mutant
• 由来する生物種: Human immunodeficiency virus 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): P03366 P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114610.50

構造登録者

Hsiou, Y.,Das, K.,Ding, J.,Arnold, E. (登録日: 1998-08-17, 公開日: 1999-01-06, 最終更新日: 2024-05-22)

主引用文献

Hsiou, Y.,Das, K.,Ding, J.,Clark Jr., A.D.,Kleim, J.P.,Rosner, M.,Winkler, I.,Riess, G.,Hughes, S.H.,Arnold, E.
Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance.
J.Mol.Biol., 284:313-323, 1998

PubMed Abstract: The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 (S-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroqui noxalin-2(1H)-thione), is an extremely potent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infection in cell culture. HBY 097 selects for unusual drug-resistance mutations in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleoside RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO. We have determined the structure of HBY 097 complexed with wild-type HIV-1 RT at 3.1 A resolution. The HIV-1 RT/HBY 097 structure reveals an overall inhibitor geometry and binding mode differing significantly from RT/NNRTI structures reported earlier, in that HBY 097 does not adopt the usual butterfly-like shape. We have determined the structure of the Tyr188Leu HIV-1 RT drug-resistant mutant in complex with HBY 097 at 3.3 A resolution. HBY 097 binds to the mutant RT in a manner similar to that seen in the wild-type RT/HBY 097 complex, although there are some repositioning and conformational alterations of the inhibitor. Conformational changes of the structural elements forming the inhibitor-binding pocket, including the orientation of some side-chains, are observed. Reduction in the size of the 188 side-chain and repositioning of the Phe227 side-chain increases the volume of the binding cavity in the Tyr188Leu HIV-1 RT/HBY 097 complex. Loss of important protein-inhibitor interactions may account for the reduced potency of HBY 097 against the Tyr188Leu HIV-1 RT mutant. The loss of binding energy may be partially offset by additional contacts resulting from conformational changes of the inhibitor and nearby amino acid residues. This would suggest that inhibitor flexibility can help to minimize drug resistance.

PubMed: 9813120
DOI: 10.1006/jmbi.1998.2171

実験手法

X-RAY DIFFRACTION (3.1 Å)