title: Effects of efavirenz binding on the subunit equilibria of HIV-1 reverse transcriptase.
abstract: Recent studies showed that nonnucleoside reverse transcriptase inhibitors (NNRTIs) have variable effects on dimerization of p66 and p51 subunits of HIV-1 reverse transcriptase (RT). Efavirenz, one of three NNRTIs currently used in highly active anti-retroviral therapy, enhances subunit dimerization. Sedimentation equilibrium experiments on each subunit and equimolar mixtures of both subunits were used to measure dissociation constants for the three coupled dimerization reactions of RT in the absence and presence of saturating concentrations of the drug. The dimerization constants of the p51/p51 homodimer, the p66/p66 homodimer, and the p66/p51 heterodimer increased 600-, 50-, and 25-fold, respectively, upon binding of efavirenz. The effects of NNRTIs on RT dimerization are consistent with a thermodynamic linkage between subunit association/dissociation and inhibitor binding. Analysis of crystal structures of the p66/p51 heterodimer reveals that efavirenz binding induces small structural changes at the dimer interface.
authors.affiliation: Department Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Venezia
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Howard
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ignatov
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Holladay
authors.forename: Mary D
authors.initials: MD
authors.lastname: Barkley
mesh_terms: D000480:Alkynes; D048588:Benzoxazines; D001665:Binding Sites; D003521:Cyclopropanes; D019281:Dimerization; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D007700:Kinetics; D010078:Oxazines / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D021122:Protein Subunits; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz