title: Allosteric modulation of anti-HIV drug and ferric heme binding to human serum albumin.
abstract: Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional capacity to bind ligands (e.g. heme and drugs). Here, binding of the anti-HIV drugs abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and zidovudine to HSA and ferric heme-HSA is reported. Ferric heme binding to HSA in the absence and presence of anti-HIV drugs was also investigated. The association equilibrium constant and second-order rate constant for the binding of anti-HIV drugs to Sudlow's site I of ferric heme-HSA are lower by one order of magnitude than those for the binding of anti-HIV drugs to HSA. Accordingly, the association equilibrium constant and the second-order rate constant for heme binding to HSA are decreased by one order of magnitude in the presence of anti-HIV drugs. In contrast, the first-order rate constant for ligand dissociation from HSA is insensitive to anti-HIV drugs and ferric heme. These findings represent clear-cut evidence for the allosteric inhibition of anti-HIV drug binding to HSA by the heme. In turn, anti-HIV drugs allosterically impair heme binding to HSA. Therefore, Sudlow's site I and the heme cleft must be functionally linked.
authors.affiliation: National Institute for Infectious Diseases I.R.C.C.S. Lazzaro Spallanzani, Roma, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Bocedi
authors.forename: Stefania
authors.initials: S
authors.lastname: Notari
authors.forename: Enea
authors.initials: E
authors.lastname: Menegatti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fanali
authors.forename: Mauro
authors.initials: M
authors.lastname: Fasano
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascenzi
mesh_terms: D000494:Allosteric Regulation; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D006418:Heme / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D012709:Serum Albumin; D006418:Heme