Reprint of "Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site" [Bioorg. Med. Chem. Lett. 18 (2008) 4554-4557]

Vladimir Yu Torbeev; Kalyaneswar Mandal; Valentina A Terechko; Stephen B H Kent

doi:10.1016/S0960-894X(08)01314-0

Reprint of "Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site" [Bioorg. Med. Chem. Lett. 18 (2008) 4554-4557]

Bioorg Med Chem Lett. 2008 Nov 15;18(22):6012-5. doi: 10.1016/S0960-894X(08)01314-0.

Authors

Vladimir Yu Torbeev¹, Kalyaneswar Mandal, Valentina A Terechko, Stephen B H Kent

Affiliation

¹ Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. torbeev@uchicago.edu

PMID: 18995173
DOI: 10.1016/S0960-894X(08)01314-0

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-Nlepsi[CO-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.