2IEO

Crystal structure analysis of HIV-1 protease mutant I84V with a potent non-peptide inhibitor (UIC-94017)

Replaces:  1S6S

Summary for 2IEO

• Entry DOI: 10.2210/pdb2ieo/pdb
• Related: 2IDW 2IEN
• Descriptor: Protease, CHLORIDE ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: hiv-1 protease, mutant, i84v, dimer, inhibitor, uic-94017, tmc114, darunavir, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22130.31

Authors

Tie, Y.,Boross, P.I.,Wang, Y.F.,Gaddis, L.,Manna, D.,Hussain, A.K.,Leshchenko, S.,Ghosh, A.K.,Louis, J.M.,Harrison, R.W.,Weber, I.T. (deposition date: 2006-09-19, release date: 2006-10-03, Last modification date: 2023-08-30)

Primary citation

Tie, Y.,Boross, P.I.,Wang, Y.F.,Gaddis, L.,Hussain, A.K.,Leshchenko, S.,Ghosh, A.K.,Louis, J.M.,Harrison, R.W.,Weber, I.T.
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-Peptide Inhibitor (Uic-94017) Active Against Multi-Drug-Resistant Clinical Strains.
J.Mol.Biol., 338:341-352, 2004

PubMed Abstract: 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.

PubMed: 15066436
DOI: 10.1016/j.jmb.2004.02.052

Experimental method

X-RAY DIFFRACTION (1.53 Å)