Document 0968
 DOCN  M9650968
 TI    Structure of HIV-1 protease with KNI-272, a tight-binding
       transition-state analog containing allophenylnorstatine.
 DT    9505
 AU    Baldwin ET; Bhat TN; Gulnik S; Liu B; Topol IA; Kiso Y; Mimoto T;
       Mitsuya H; Erickson JW; Frederick Biomedical Supercomputing Center,
       SAIC-Frederick,; NCI-Frederick Cancer Research and Development Center,
       Maryland; 21702, USA.
 SO    Structure. 1995 Jun 15;3(6):581-90. Unique Identifier : AIDSLINE
       MED/96173007
 AB    BACKGROUND: HIV-1 protease (HIV PR), an aspartic protease, cleaves
       Phe-Pro bonds in the Gag and Gag-Pol viral polyproteins. Substrate-based
       peptide mimics constitute a major class of inhibitors of HIV PR
       presently being developed for AIDS treatment. One such compound,
       KNI-272, which incorporates allophenylnorstatine (Apns)-thioproline
       (Thp) in place of Phe-Pro, has potent antiviral activity and is
       undergoing clinical trials. The structure of the enzyme-inhibitor
       complex should lead to an understanding of the structural basis for its
       tight binding properties and provide a framework for interpreting the
       emerging resistance to this drug. RESULTS: The three-dimensional crystal
       structure of KNI-272 bound to HIV PR has been determined to 2.0 A
       resolution and used to analyze structure-activity data and drug
       resistance for the Arg8-->Gln and ILe84-->Val mutations in HIV PR. The
       conformationally constrained Apns-Thp linkage is favorably recognized in
       its low energy trans conformation, which results in a symmetric mode of
       binding to the active-site aspartic acids and also explains the unusual
       preference of HIV PR for the S, or syn, hydroxyl group of the Apns
       residue. The inhibitor recognizes the enzyme via hydrogen bonds to three
       bridging water molecules, including one that is coordinated directly to
       the catalytic Asp125 residue. CONCLUSIONS: The structure of the HIV
       PR/KNI-272 complex illustrates the importance of limiting the
       conformational degrees of freedom and of using protein-bound water
       molecules for building potent inhibitors. The binding mode of HIV PR
       inhibitors can be predicted from the stereochemical relationship between
       adjacent hydroxyl-bearing and side chain bearing carbon atoms of the P1
       substituent. Our structure also provides a framework for designing
       analogs targeted to drug-resistant mutant enzymes.
 DE    Amino Acid Sequence  Antiviral Agents/CHEMISTRY/METABOLISM/PHARMACOLOGY
       Binding Sites  Comparative Study  Crystallography, X-Ray  Drug
       Resistance, Microbial  Hydrogen  HIV Protease/*CHEMISTRY/*METABOLISM
       HIV Protease Inhibitors/CHEMISTRY/*METABOLISM/PHARMACOLOGY  Molecular
       Sequence Data  Oligopeptides/*CHEMISTRY/METABOLISM/*PHARMACOLOGY
       Phenylbutyrates/*CHEMISTRY/METABOLISM  Proline/CHEMISTRY  Protein
       Conformation  Structure-Activity Relationship
       Water/CHEMISTRY/METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).