2idw

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spinqualitylabelsall models 2idw, resolution 1.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure analysis of HIV-1 protease mutant V82A with a potent non-peptide inhibitor (UIC-94017)

Overview

The compound UIC-94017 (TMC-114) is a second-generation HIV protease, inhibitor with improved pharmacokinetics that is chemically related to the, clinical inhibitor amprenavir. UIC-94017 is a broad-spectrum potent, inhibitor active against HIV-1 clinical isolates with minimal, cytotoxicity. We have determined the high-resolution crystal structures of, UIC-94017 in complexes with wild-type HIV-1 protease (PR) and mutant, proteases PR(V82A) and PR(I84V) that are common in drug-resistant HIV. The, structures were refined at resolutions of 1.10-1.53A. The crystal, structures of PR and PR(I84V) with UIC-94017 ternary complexes show that, the inhibitor binds to the protease in two overlapping positions, while, the PR(V82A) complex had one ordered inhibitor. In all three structures, UIC-94017 forms hydrogen bonds with the conserved main-chain atoms of, Asp29 and Asp30 of the protease. These interactions are proposed to be, critical for the potency of this compound against HIV isolates that are, resistant to multiple protease inhibitors. Other small differences were, observed in the interactions of the mutants with UIC-94017 as compared to, PR. PR(V82A) showed differences in the position of the main-chain atoms of, residue 82 compared to PR structure that better accommodated the, inhibitor. Finally, the 1.10A resolution structure of PR(V82A) with, UIC-94017 showed an unusual distribution of electron density for the, catalytic aspartate residues, which is discussed in relation to the, reaction mechanism.

About this Structure

2IDW is a Single protein structure of sequence from Human immunodeficiency virus 1 with CL, PO4, 017, DMS, ACY and GOL as ligands. This structure superseeds the now removed PDB entry 1S65. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains., Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2004 Apr 23;338(2):341-52. PMID:15066436

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