Pinto, Cibele and Lushington, Gerald H. and Richter, Mark and Gille, Andreas and Geduhn, Jens and Koenig, Burkhard and Mou, Tung-Chung and Sprang, Stephen R. and Seifert, Roland (2011) Structure-activity relationships for the interactions of 2 '- and 3 '-(O)-(N-methyl)anthraniloyl-substituted purine and pyrimidine nucleotides with mammalian adenylyl cyclases. BIOCHEMICAL PHARMACOLOGY, 82 (4). pp. 358-370. ISSN 0006-2952, 1873-2968
Full text not available from this repository. (Request a copy)Abstract
Membranous adenylyl cyclases (ACs) play a key role in signal transduction and are promising drug targets. In previous studies we showed that 2',3'-(O)-(N-methylanthraniloyl) (MANT)-substituted nucleotides are potent AC inhibitors. The aim of this study was to provide systematic structure-activity relationships for 21 (M)ANT-substituted nucleotides at the purified catalytic AC subunit heterodimer VC1:IIC2, the VC1:VC1 homodimer and recombinant ACs 1, 2 and 5. (M)ANT-nucleotides inhibited fully activated VC1:IIC2 in the order of affinity for bases hypoxanthine > uracil > cytosine > adenine similar to guanine >> xanthine. Omission of a hydroxyl group at the 2' or 3'-position reduced inhibitor potency as did introduction of a gamma-thiophosphate group or omission of the gamma-phosphate group. Substitution of the MANT-group by an ANT-group had little effect on affinity. Although all nucleotides bound to VC1:IIC2 similarly according to the tripartite pharmacophore model with a site for the base, the ribose, and the phosphate chain, nucleotides exhibited subtle differences in their binding modes as revealed by fluorescence spectroscopy and molecular modelling. MANT-nucleotides also differentially interacted with the VC1:VC1 homodimer as assessed by fluorescence spectroscopy and modelling. Similar structure-activity relationships as for VC1:IIC2 were obtained for recombinant ACs 1,2 and 5, with AC2 being the least sensitive AC isoform in terms of inhibition. Overall, ACs possess a broad base-specificity with no preference for the "cognate" base adenine as verified by enzyme inhibition, fluorescence spectroscopy and molecular modelling. These properties of ACs are indicative for ligand-specific conformational landscapes that extend to the VC1:VC1 homodimer and should facilitate development of non-nucleotide inhibitors. (C) 2011 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SOLUBLE GUANYLYL CYCLASE; NUCLEOSIDE 5'-TRIPHOSPHATES; EDEMA FACTOR; DIFFERENTIAL INTERACTIONS; BACILLUS-ANTHRACIS; FORSKOLIN ANALOGS; DRUG DISCOVERY; ISOFORMS; INHIBITION; PROTEIN; Adenylyl Cyclase; MANT-nucleotides; Fluorescence spectroscopy; Molecular modelling; Conformational landscape |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Jun 2020 05:27 |
| Last Modified: | 03 Jun 2020 05:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20399 |
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