title: A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.
abstract: Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, cancer, and psychosis. Ribose-substituted nucleotides have been reported as a potent family of AC inhibitors. In silico analysis of the docked conformers of such nucleotides in AC permits assembly of a consistent, intuitive QSAR model with strong correlation relative to measured pK(i) values. Energy decomposition suggests that the MANT group effects an AC conformational transition upon ligand binding.
authors.affiliation: Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Wang
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Guo
authors.forename: Qi-Yuan
authors.initials: QY
authors.lastname: Zhang
authors.forename: Jay J-Q
authors.initials: JJ
authors.lastname: Wu
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D012266:Ribose
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D007202:Indicators and Reagents; D008024:Ligands; D009711:Nucleotides; D010710:Phosphates; D011687:Purines; D011743:Pyrimidines; D012266:Ribose; D000262:Adenylyl Cyclases