       Document 0037
 DOCN  M9470037
 TI    Sensitivity of wild-type human immunodeficiency virus type 1 reverse
       transcriptase to dideoxynucleotides depends on template length; the
       sensitivity of drug-resistant mutants does not.
 DT    9409
 AU    Boyer PL; Tantillo C; Jacobo-Molina A; Nanni RG; Ding J; Arnold E;
       Hughes SH; Advanced BioScience Laboratories-Basic Research Program,
       National; Cancer Institute-Frederick Cancer Research and Development;
       Center, MD 21702-1201.
 SO    Proc Natl Acad Sci U S A. 1994 May 24;91(11):4882-6. Unique Identifier :
       AIDSLINE MED/94255432
 AB    Analysis of the three-dimensional structure of human immunodeficiency
       virus type 1 (HIV-1) reverse transcriptase (RT) complexed with
       double-stranded DNA indicates that while many nucleoside-resistance
       mutations are not at the putative dNTP binding site, several are in
       positions to interact with the template-primer. Wild-type HIV-1 RT and
       two nucleoside-resistant variants, Leu74-->Val and Glu89-->Gly, have
       been analyzed to determine the basis of resistance. The ability of the
       wild-type enzyme to incorporate, or reject, a 2',3'-dideoxynucleoside
       triphosphate (ddNTP) is strongly affected by interactions that take
       place between the enzyme and the extended template strand 3-6 nt beyond
       the polymerase active site. Inspection of a model of the enzyme with an
       extended template suggests that this interaction involves the fingers
       subdomain of the p66 subunit in the vicinity of Leu74. These data
       provide direct evidence that the fingers subdomain of the p66 subunit of
       HIV-1 RT interacts with the template strand. The wild-type enzyme is
       resistant to ddITP if the template extension is 3 nt or less and becomes
       sensitive only when the template extends more than 3 or 4 nt beyond the
       end of the primer strand. However, the mutant enzymes are resistant with
       both short and long template extensions. Taken together with the
       three-dimensional structure of HIV-1 RT in complex with double-stranded
       DNA, these data suggest that resistance to the dideoxynucleotide
       inhibitors results from a repositioning or change in the conformation of
       the template-primer that alters the ability of the enzyme to select or
       reject an incoming dNTP.
 DE    Base Sequence  Dideoxynucleosides/*PHARMACOLOGY  Drug Resistance,
       Microbial/GENETICS  DNA, Viral  Molecular Sequence Data  Protein
       Conformation  Reverse Transcriptase/CHEMISTRY/*DRUG EFFECTS/GENETICS
       Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Templates  JOURNAL
       ARTICLE

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

