Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site |
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Authors: | Torbeev Vladimir Yu Mandal Kalyaneswar Terechko Valentina A Kent Stephen B H |
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Institution: | Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. torbeev@uchicago.edu |
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Abstract: | Here we report the X-ray structures of chemically synthesized HIV-1 protease and the inactive D25N]HIV-1 protease complexed with the ketomethylene isostere inhibitor Ac-Thr-Ile-Nle psiCO-CH(2)]Nle-Gln-Arg.amide at 1.4 and 1.8A resolution, respectively. In complex with the active enzyme, the keto-group was found to be converted into the hydrated gem-diol, while the structure of the complex with the inactive D25N enzyme revealed an intact keto-group. These data support the general acid-general base mechanism for HIV-1 protease catalysis. |
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