title: Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site.
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 psi[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.
authors.affiliation: Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. torbeev@uchicago.edu
authors.forename: Vladimir Yu
authors.initials: VY
authors.lastname: Torbeev
authors.forename: Kalyaneswar
authors.initials: K
authors.lastname: Mandal
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Terechko
authors.forename: Stephen B H
authors.initials: SB
authors.lastname: Kent
mesh_terms: D020134:Catalytic Domain; D002627:Chemistry, Physical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism*; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D019251:Nucleocapsid / Q000737:chemistry*; D010446:Peptide Fragments / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000737:chemistry; D011487:Protein Conformation; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D017320:HIV Protease Inhibitors; D010446:Peptide Fragments; D054301:gag Gene Products, Human Immunodeficiency Virus; C109809:p2 gag peptide, Human immunodeficiency virus 1; D010447:Peptide Hydrolases; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1