3SPK

Tipranavir in Complex with a Human Immunodeficiency Virus Type 1 Protease Variant

3SPK の概要

• エントリーDOI: 10.2210/pdb3spk/pdb
• 関連するPDBエントリー: 1RPI 1TW7 3OQ7 3OQA 3OQD 3SO9
• 分子名称: HIV-1 protease, N-(3-{(1R)-1-[(6R)-4-HYDROXY-2-OXO-6-PHENETHYL-6-PROPYL-5,6-DIHYDRO-2H-PYRAN-3-YL]PROPYL}PHENYL)-5-(TRIFLUOROMETHYL)-2-PYRIDINESULFONAMIDE (3 entities in total)
• 機能のキーワード: tipranavir, multi-drug resistant hiv-1 protease, hydorlase-hydorlase inhibitor complex, hydorlase/hydorlase inhibitor
• 由来する生物種: human immunodeficiency virus type 1 (HIV)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22746.70

構造登録者

Wang, Y.,Liu, Z.,Brunzelle, J.S.,Kovari, I.A.,Kovari, L.C. (登録日: 2011-07-01, 公開日: 2011-10-12, 最終更新日: 2024-02-28)

主引用文献

Wang, Y.,Liu, Z.,Brunzelle, J.S.,Kovari, I.A.,Dewdney, T.G.,Reiter, S.J.,Kovari, L.C.
The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.
Biochem.Biophys.Res.Commun., 412:737-742, 2011

PubMed Abstract: Darunavir and tipranavir are two inhibitors that are active against multi-drug resistant (MDR) HIV-1 protease variants. In this study, the invitro inhibitory efficacy was tested against a MDR HIV-1 protease variant, MDR 769 82T, containing the drug resistance mutations of 46L/54V/82T/84V/90M. Crystallographic and enzymatic studies were performed to examine the mechanism of resistance and the relative maintenance of potency. The key findings are as follows: (i) The MDR protease exhibits decreased susceptibility to all nine HIV-1 protease inhibitors approved by the US Food and Drug Administration (FDA), among which darunavir and tipranavir are the most potent; (ii) the threonine 82 mutation on the protease greatly enhances drug resistance by altering the hydrophobicity of the binding pocket; (iii) darunavir or tipranavir binding facilitates closure of the wide-open flaps of the MDR protease; and (iv) the remaining potency of tipranavir may be preserved by stabilizing the flaps in the inhibitor-protease complex while darunavir maintains its potency by preserving protein main chain hydrogen bonds with the flexible P2 group. These results could provide new insights into drug design strategies to overcome multi-drug resistance of HIV-1 protease variants.

PubMed: 21871444
DOI: 10.1016/j.bbrc.2011.08.045

実験手法

X-RAY DIFFRACTION (1.24 Å)