       Document 0282
 DOCN  M9640282
 TI    The structure of HIV-1 reverse transcriptase complexed with
       9-chloro-TIBO: lessons for inhibitor design.
 DT    9604
 AU    Ren J; Esnouf R; Hopkins A; Ross C; Jones Y; Stammers D; Stuart D;
       Laboratory of Molecular Biophysics, Oxford, UK.
 SO    Structure. 1995 Sep 15;3(9):915-26. Unique Identifier : AIDSLINE
       MED/96097398
 AB    BACKGROUND: HIV reverse transcriptase (RT) is a key target of anti-AIDS
       therapies. Structural studies of HIV-1 RT, unliganded and complexed with
       different non-nucleoside inhibitors (NNIs), have pointed to a common
       mode of binding and inactivation through distortion of the polymerase
       catalytic site by NNIs containing two hinged rings. The mode of binding
       of the TIBO family of inhibitors is of interest because these compounds
       do not fit the two-hinged-ring model. RESULTS: The structure of HIV-1 RT
       complexed with 9-chloro-TIBO (R82913) has been determined at 2.6 A
       resolution. As reported for the lower resolution analysis of another
       TIBO compound, this inhibitor binds at the same site as other NNIs, but
       our higher resolution study reveals the Cl-TIBO is distorted from the
       conformation seen in crystals of the inhibitor alone. This allows
       Cl-TIBO to mimic the binding of NNIs containing two hinged rings.
       Inhibitor-protein interactions are again predominantly hydrophobic and
       the protein conformation corresponds to that seen in complexes with
       other tight-binding NNIs. CONCLUSIONS: Although Cl-TIBO is chemically
       very different from other NNIs, it achieves remarkable spatial
       equivalence and shape complementarity with other NNIs on binding to RT.
       Comparison of the different RT-NNI complexes suggests modifications to
       the TIBO group of inhibitors which might enhance their binding and
       hence, potentially, their therapeutic efficacy.
 DE    Benzodiazepines/*CHEMISTRY/METABOLISM  Binding Sites  Comparative Study
       Crystallography, X-Ray  Drug Resistance, Microbial/GENETICS
       HIV-1/*ENZYMOLOGY  Imidazoles/*CHEMISTRY/METABOLISM  Metals/METABOLISM
       Models, Molecular  Mutation  Protein Conformation
       Pyridines/CHEMISTRY/METABOLISM  Reverse Transcriptase
       Inhibitors/CHEMISTRY/METABOLISM  Ribonuclease H, Calf Thymus/METABOLISM
       RNA-Directed DNA Polymerase/*CHEMISTRY/GENETICS/METABOLISM  Support,
       Non-U.S. Gov't  Thymine/ANALOGS & DERIVATIVES/CHEMISTRY/METABOLISM
       JOURNAL ARTICLE

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

