Dataset Information

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.

SUBMITTER: Wang JL

PROVIDER: S-EPMC2023969 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.

Wang Jenna L JL Guo Jian-Xin JX Zhang Qi-Yuan QY Wu Jay J-Q JJ Seifert Roland R Lushington Gerald H GH

Bioorganic & medicinal chemistry 20070211 8

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. ...[more]

PMID: 17329110

Similar Datasets

Project description:The diterpene forskolin (FS) binds to, and activates, mammalian membranous adenylyl cyclase (AC) isoforms I-VIII. Diterpenes without C(1)-OH group do not activate ACs. The C(1)-OH group forms a hydrogen bond with the backbone oxygen of Val506 of the C1 catalytic subunit of AC (isoform V numbering). To better understand the mechanism of AC activation we examined the interactions of FS and eight FS analogs with purified catalytic AC subunits C1 (AC V) and C2 (AC II) by fluorescence spectroscopy, using 2',3'-O-(N-methylanthraniloyl)-guanosine 5'-triphosphate (MANT-GTP) as fluorescent reporter probe, and by enzymatic activity. FS analogs induced C1/C2 assembly as assessed by fluorescence resonance energy transfer from Trp1020 of C2 to MANT-GTP and by increased direct MANT-GTP fluorescence in the order of efficacy FS approximately 7-deacetyl-FS approximately 6-acetyl-7-deacetyl-FS approximately 9-deoxy-FS>7-deacetyl-7-(N-methylpiperazino-gamma-butyryloxy)-FS>1-deoxy-FS approximately 1,9-dideoxy-FS approximately 7-deacetyl-1-deoxy-FS approximately 7-deacetyl-1,9-dideoxy-FS. In contrast, FS analogs activated catalysis in the order of efficacy FS>7-deacety-FS approximately 6-acetyl-7-deacetyl-FS approximately 9-deoxy-FS>7-deacetyl-7-(N-methylpiperazino-gamma-butyryloxy)-FS>>1-deoxy-FS, 1,9-dideoxy-FS, 7-deacetyl-1-deoxy-FS and 7-deacetyl-1,9-dideoxy-FS (all ineffective). 1-Deoxy-FS analogs inhibited FS-stimulated catalysis by an apparently non-competitive mechanism. Our data suggest a two-step mechanism of AC activation by diterpenes. In the first step, diterpenes, regardless of their substitution pattern, promote C1/C2 assembly. In the second and yet poorly understood step, diterpenes that form a hydrogen bond between C(1)-OH and Val506 promote a conformational switch that results in activation of catalysis. The apparent non-competitive interaction of FS with 1-deoxy-FS analogs is explained by impaired ligand exchange due to strong hydrophobic interactions with C1/C2.

Dataset Information

A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.

Publications

A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets