Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV type 1 (HIV-1) reverse transcriptase (RT). Yeast grown in the presence of many of these drugs exhibited dramatically increased association of the p66 and p51 subunits of the HIV-1 RT as reported by a yeast two-hybrid assay. The enhancement required drug binding by RT; introduction of a drug-resistance mutation into the p66 construct negated the enhancement effect. The drugs could also induce heterodimerization of dimerization defective mutants. Coimmunoprecipitation of RT subunits from yeast lysates confirmed the induction of heterodimer formation by the drugs. In vitro-binding studies indicate that NNRTIs can bind tightly to p66 but not p51 and then mediate subsequent heterodimerization. This study demonstrates an unexpected effect of NNRTIs on the assembly of RT subunits.
Tachedjian
G
G
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA.
Orlova
M
M
Sarafianos
S G
SG
Arnold
E
E
Goff
S P
SP
D019943:Amino Acid Substitution; D001665:Binding Sites; D019281:Dimerization; D004352:Drug Resistance, Microbial / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase