title: Correlating conformational shift induction with altered inhibitor potency in a multidrug resistant HIV-1 protease variant.
abstract: Inhibitor-induced conformational ensemble shifts in a multidrug resistant HIV-1 protease variant, MDR769, are characterized by site-directed spin labeling double electron-electron resonance spectroscopy. For MDR769 compared to the native enzyme, changes in inhibitor IC(50) values are related to a parameter defined as |ΔC|, which is the relative change in the inhibitor-induced shift to the closed state. Specifically, a linear correlation is found between |ΔC| and the magnitude of the change in IC(50), provided that inhibitor binding is not too weak. Moreover, inhibitors that exhibit MDR769 resistance no longer induce a strong shift to a closed conformational ensemble as seen previously in the native enzyme.
authors.affiliation: Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, USA.
authors.forename: Ian Mitchelle S
authors.initials: IM
authors.lastname: de Vera
authors.forename: Mandy E
authors.initials: ME
authors.lastname: Blackburn
authors.forename: Gail E
authors.initials: GE
authors.lastname: Fanucci
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D024921:Drug Resistance, Multiple, Viral; D004578:Electron Spin Resonance Spectroscopy; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D014644:Genetic Variation; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D013113:Spin Labels
chemical_list: D019380:Anti-HIV Agents; D013113:Spin Labels; D016333:HIV Protease