Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere

Background: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and th...

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Bibliographic Details
Published in:Structure (London) 1995-01, Vol.3 (1), p.33-40
Main Authors: Tong, Liang, Pav, Susan, Mui, Suet, Lamarre, Daniel, Yoakim, Christiane, Beaulieu, Pierre, Anderson, Paul C
Format: Article
Language:English
Subjects:
Acquired Immunodeficiency Syndrome - drug therapy
AIDS
AIDS/HIV
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - chemistry
aspartic proteases
Binding Sites
Crystallography, X-Ray
Dipeptides - chemistry
Dipeptides - pharmacology
Drug Design
HIV Protease
HIV-2 - enzymology
Humans
Macromolecular Substances
Models, Molecular
Molecular Conformation
peptidomimetic inhibitors
Pipecolic Acids - chemistry
Pipecolic Acids - pharmacology
Protease Inhibitors - chemistry
Protein Conformation
retrovirus
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Summary:Background: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors. Results We report here crystal structures at up to 1.7 Å resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48′ and 49′ in the flap of the protease and residues 29′ and 30′ (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. Conclusion This study shows that besides the residues in the flap and residues 79–81 in the S 1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.
ISSN:0969-2126
1878-4186
DOI:10.1016/S0969-2126(01)00133-2