       Document 0033
 DOCN  M9460033
 TI    Structure of the binding site for nonnucleoside inhibitors of the
       reverse transcriptase of human immunodeficiency virus type 1.
 DT    9408
 AU    Smerdon SJ; Jager J; Wang J; Kohlstaedt LA; Chirino AJ; Friedman JM;
       Rice PA; Steitz TA; Department of Molecular Biophysics and Biochemistry,
       Howard; Hughes Medical Institute, Yale University, New Haven, CT 06511.
 SO    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3911-5. Unique Identifier :
       AIDSLINE PDB/2HVT
 AB    The dipyridodiazepinone Nevirapine is a potent and highly specific
       inhibitor of the reverse transcriptase (RT) from human immunodeficiency
       virus type 1 (HIV-1). It is a member of an important class of
       nonnucleoside drugs that appear to share part or all of the same binding
       site on the enzyme but are susceptible to a variety of spontaneous
       drug-resistance mutations. The co-crystal-structure of HIV-1 RT and
       Nevirapine has been solved previously at 3.5-A resolution and now is
       partially refined against data extending to 2.9-A spacing. The drug is
       bound in a hydrophobic pocket and in contact with some 38 protein atoms
       from the p66 palm and thumb subdomains. Most, but not all, nonnucleoside
       drug-resistance mutations map to residues in close contact with
       Nevirapine. The major effects of these mutations are to introduce steric
       clashes with the drug molecule or to remove favorable protein-drug
       contacts. Additionally, four residues (Phe-227, Trp-229, Leu-234, and
       Tyr-319) in contact with Nevirapine have not been selected as sites of
       drug-resistance mutations, implying that there may be limitations on the
       number and types of resistance mutations that yield viable virus.
       Strategies of inhibitor design that target interactions with these
       conserved residues may yield drugs that are less vulnerable to escape
       mutations.
 DE    Amino Acid Sequence  Antiviral Agents/CHEMISTRY  Binding Sites  Drug
       Resistance, Microbial  HIV-1/ENZYMOLOGY  Models, Molecular  Molecular
       Sequence Data  Molecular Structure  Nucleosides/CHEMISTRY  Protein
       Structure, Tertiary  Pyridines/*CHEMISTRY  Reverse
       Transcriptase/*ANTAGONISTS & INHIB/ULTRASTRUCTURE  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).

