Open AccessStructure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design
Author(s) -
Yehuda Goldgur,
Robert Craigie,
Gerald Cohen,
Tamio Fujiwara,
Tomokazu Yoshinaga,
Toshio Fujishita,
H. Sugimoto,
Takeshi Endo,
Hitoshi Murai,
David R. Davies
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.23.13040
Subject(s) - integrase , reverse transcriptase , integrase inhibitor , enzyme , protease inhibitor (pharmacology) , virology , viral protein , chemistry , enzyme inhibitor , biology , active site , biochemistry , human immunodeficiency virus (hiv) , virus , viral load , rna , antiretroviral therapy , gene
HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H -tetrazol-5-yl)-propenone, to 2.1-Å resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.