title: The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors.
abstract: Specific HIV integrase strand transfer inhibitors are thought to bind to the integrase active site, positioned to coordinate with two catalytic magnesium atoms in a pocket flanked by the end of the viral LTR. A structural role for the 3' terminus of the viral LTR in the inhibitor-bound state has not previously been examined. This study describes the kinetics of binding of a specific strand transfer inhibitor to integrase variants assembled with systematic changes to the terminal 3' adenosine. Kinetic experiments are consistent with a two-step binding model in which there are different functions for the terminal adenine base and the terminal deoxyribose sugar. Adenine seems to act as a "shield" which retards the rate of inhibitor association with the integrase active site, possibly by acting as an internal competitive inhibitor. The terminal deoxyribose is responsible for retarding the rate of inhibitor dissociation, either by sterically blocking inhibitor egress or by a direct interaction with the bound inhibitor. These findings further our understanding of the details of the inhibitor binding site of specific strand transfer inhibitors.
authors.affiliation: Department of Computer Assisted Drug Design, Bristol-Myers Squibb Research & Development, Wallingford, Connecticut 06492, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Himadri K
authors.initials: HK
authors.lastname: Samanta
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Lin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walker
authors.forename: Mark R
authors.initials: MR
authors.lastname: Krystal
authors.forename: Ira B
authors.initials: IB
authors.lastname: Dicker
mesh_terms: D020413:3' Untranslated Regions; D000241:Adenosine / Q000737:chemistry; D001667:Binding, Competitive; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006678:HIV / Q000235:genetics; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013696:Temperature
chemical_list: D020413:3' Untranslated Regions; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; D000241:Adenosine