High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains

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• 作者：Tie ; Yunfeng ; Boross ; Peter I. ; Wang ; Yuan-Fang ; Gaddis ; Laquasha ; Hussain ; Azhar K. ; Leshchenko ; Sofiya ; et. al.
• 关键词：HIV protease ; crystal structure ; drug resistance ; catalysis ; PR ; wild-type HIV-1 protease ; PR_V82A ; PR with V82A mutation ; PR_I84V ; PR with I84V mutation ; DMSO ; dimethylsulfoxide
• 刊名：Journal of Molecular Biology
• 出版年：2004
• 出版时间：April 23, 2004
• 年：2004
• 卷：338
• 期：2
• 页码：341-352
• 全文大小：2.28 M

文摘

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 1.10–1.53Å. 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 1.10Å 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.