Structure-Activity Relationships for the Interactions of 2’- and 3’-(O)-(N-Methyl)anthraniloyl-Substituted Purine and Pyrimidine Nucleotides with Mammalian Adenylyl Cyclases
dc.contributor.author | Pinto, Cibele | |
dc.contributor.author | Lushington, Gerald H. | |
dc.contributor.author | Richter, Mark | |
dc.contributor.author | Gille, Andreas | |
dc.contributor.author | Geduhn, Jens | |
dc.contributor.author | Konig, Burkhard | |
dc.contributor.author | Mou, Tung-Chung | |
dc.contributor.author | Sprang, Stephen R. | |
dc.contributor.author | Seifert, Roland | |
dc.date.accessioned | 2017-01-27T20:38:15Z | |
dc.date.available | 2017-01-27T20:38:15Z | |
dc.date.issued | 2011-05-18 | |
dc.identifier.citation | Pinto, Cibele, Gerald H. Lushington, Mark Richter, Andreas Gille, Jens Geduhn, Burkhard König, Tung-Chung Mou, Stephen R. Sprang, and Roland Seifert. "Structureâ activity Relationships for the Interactions of 2â ²- and 3â ²-(O)-(N-methyl)anthraniloyl-substituted Purine and Pyrimidine Nucleotides with Mammalian Adenylyl Cyclases." Biochemical Pharmacology 82.4 (2011): 358-70. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/22685 | |
dc.description.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 ~ guanine ≫ xanthine. Omission of a hydroxyl group at the 2’ or 3’-position reduced inhibitor potency as did introduction of a γ-thiophosphate group or omission of the γ-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. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject | Adenylyl cyclase | en_US |
dc.subject | MANT-nucleotide | en_US |
dc.subject | Fluorescence spectroscopy | en_US |
dc.subject | Molecular modelling | en_US |
dc.subject | Conformational landscape | en_US |
dc.title | Structure-Activity Relationships for the Interactions of 2’- and 3’-(O)-(N-Methyl)anthraniloyl-Substituted Purine and Pyrimidine Nucleotides with Mammalian Adenylyl Cyclases | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Richter, Mark | |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.1016/j.bcp.2011.05.010 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.