3SPK

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

Summary for 3SPK

• Entry DOI: 10.2210/pdb3spk/pdb
• Related: 1RPI 1TW7 3OQ7 3OQA 3OQD 3SO9
• Descriptor: 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)
• Functional Keywords: tipranavir, multi-drug resistant hiv-1 protease, hydorlase-hydorlase inhibitor complex, hydorlase/hydorlase inhibitor
• Biological source: human immunodeficiency virus type 1 (HIV)
• Total number of polymer chains: 2
• Total formula weight: 22746.70

Authors

Wang, Y.,Liu, Z.,Brunzelle, J.S.,Kovari, I.A.,Kovari, L.C. (deposition date: 2011-07-01, release date: 2011-10-12, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.24 Å)