3spk | pdb_00003spk

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

spinqualitylabelsall models 3spk, resolution 1.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3spk is a 2 chain structure with sequence from 9hiv1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: TPV Related: 1tw7, 1rpi, 3oq7, 3oqa, 3oqd, 3so9 Gene: pol (9HIV1) Activity: HIV-1 retropepsin, with EC number 3.4.23.16 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.,Wang Y, Liu Z, Brunzelle JS, Kovari IA, Dewdney TG, Reiter SJ, Kovari LC Biochem Biophys Res Commun. 2011 Sep 9;412(4):737-42. Epub 2011 Aug 17. PMID:21871444 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Immunodeficiency virus protease 3D structures

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