       Document 0865
 DOCN  M95A0865
 TI    Structure of HIV-1 reverse transcriptase in a complex with the
       non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution.
 DT    9510
 AU    Ding J; Das K; Tantillo C; Zhang W; Clark AD Jr; Jessen S; Lu X; Hsiou
       Y; Jacobo-Molina A; Andries K; et al; Center for Advanced Biotechnology
       and Medicine (CABM),; Piscataway, NJ 08854-5638, USA.
 SO    Structure. 1995 Apr 15;3(4):365-79. Unique Identifier : AIDSLINE
       MED/95338599
 AB    BACKGROUND: HIV-1 reverse transcriptase (RT) is a multifunctional enzyme
       that copies the RNA genome of HIV-1 into DNA. It is a heterodimer
       composed of a 66 kDa (p66) and a 51 kDa (p51) subunit. HIV-1 RT is a
       crucial target for structure-based drug design, and potent inhibitors
       have been identified, whose efficacy, however, is limited by drug
       resistance. RESULTS: The crystal structure of HIV-1 RT in complex with
       the non-nucleoside inhibitor alpha-anilinophenyl-acetamide (alpha-APA)
       R95845 has been determined at 2.8 A resolution. The inhibitor binds in a
       hydrophobic pocket near the polymerase active site. The pocket contains
       five aromatic amino acid residues and the interactions of the side
       chains of these residues with the aromatic rings of non-nucleoside
       inhibitors appear to be important for inhibitor binding. Most of the
       amino acid residues where mutations have been correlated with high
       levels of resistance to non-nucleoside inhibitors of HIV-1 RT are
       located close to alpha-APA. The overall fold of HIV-1 RT in complex with
       alpha-APA is similar to that found when in complex with nevirapine,
       another non-nucleoside inhibitor, but there are significant
       conformational changes relative to an HIV-1 RT/DNA/Fab complex.
       CONCLUSIONS: The non-nucleoside inhibitor-binding pocket has a flexible
       structure whose mobility may be required for effective polymerization,
       and may be part of a hinge that permits relative movements of two
       subdomains of the p66 subunit denoted the 'palm' and 'thumb'. An
       understanding of the structure of the inhibitor-binding pocket, of the
       interactions between HIV-1 RT and alpha-APA, and of the locations of
       mutations that confer resistance to inhibitors provides a basis for
       structure-based design of chemotherapeutic agents for the treatment of
       AIDS.
 DE    Acetamides/CHEMISTRY/*METABOLISM/PHARMACOLOGY
       Acetophenones/CHEMISTRY/*METABOLISM/PHARMACOLOGY  Amino Acid Sequence
       Antiviral Agents/CHEMISTRY/*METABOLISM/PHARMACOLOGY  Binding Sites
       Comparative Study  Crystallography, X-Ray  Deoxyuracil
       Nucleotides/METABOLISM  Drug Resistance, Microbial  Fourier Analysis
       HIV Antibodies/METABOLISM  Immunoglobulins, Fab/METABOLISM
       Methylmercury Compounds/METABOLISM  *Models, Molecular  Molecular
       Sequence Data  Organomercury Compounds/METABOLISM  Protein Binding
       *Protein Conformation  Reverse Transcriptase/ANTAGONISTS &
       INHIB/CHEMISTRY/IMMUNOLOGY/  *METABOLISM  Sequence Alignment  Sequence
       Homology, Amino Acid  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       Non-P.H.S.  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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

