       Document 0864
 DOCN  M95A0864
 TI    Comparative analysis of the X-ray structures of HIV-1 and HIV-2
       proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor.
 DT    9510
 AU    Priestle JP; Fassler A; Rosel J; Tintelnot-Blomley M; Strop P; Grutter
       MG; Department of Core Drug Discovery Technologies, Pharma Research,;
       Ciba-Geigy Ltd., Basel, Switzerland.
 SO    Structure. 1995 Apr 15;3(4):381-9. Unique Identifier : AIDSLINE
       MED/95338600
 AB    BACKGROUND: The human immunodeficiency virus (HIV) is the causative
       agent of acquired immunodeficiency syndrome (AIDS). Two subtypes of the
       virus, HIV-1 and HIV-2, have been characterized. The protease enzymes
       from these two subtypes, which are aspartic acid proteases and have been
       found to be essential for maturation of the infectious particle, share
       about 50% sequence identity. Differences in substrate and inhibitor
       binding between these enzymes have been previously reported. RESULTS: We
       report the X-ray crystal structures of both HIV-1 and HIV-2 proteases
       each in complex with the pseudosymmetric inhibitor, CGP 53820, to 2.2 A
       and 2.3 A, respectively. In both structures, the entire enzyme and
       inhibitor could be located. The structures confirmed earlier modeling
       studies. Differences between the CGP 53820 inhibitory binding constants
       for the two enzymes could be correlated with structural differences.
       CONCLUSIONS: Minor sequence changes in subsites at the active site can
       explain some of the observed differences in substrate and inhibitor
       binding between the two enzymes. The information gained from this
       investigation may help in the design of equipotent HIV-1/HIV-2 protease
       inhibitors.
 DE    Amino Acid Sequence  Aspartic Proteinases/CHEMISTRY/*METABOLISM
       Benzylamines/CHEMISTRY/*METABOLISM/PHARMACOLOGY  Binding Sites
       Comparative Study  *Crystallography, X-Ray  Hydrogen Bonding  HIV
       Protease/CHEMISTRY/*METABOLISM  HIV Protease
       Inhibitors/CHEMISTRY/*METABOLISM/PHARMACOLOGY  *Models, Molecular
       *Molecular Conformation  Molecular Sequence Data  Protein Binding
       *Protein Conformation  Sequence Alignment  Sequence Homology, Amino Acid
       Valine/*ANALOGS & DERIVATIVES/CHEMISTRY/METABOLISM/PHARMACOLOGY  JOURNAL
       ARTICLE

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

