1. Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
- Author
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Ramos-Espiritu L, Kleinboelting S, Navarrete FA, Alvau A, Visconti PE, Valsecchi F, Starkov A, Manfredi G, Buck H, Adura C, Zippin JH, van den Heuvel J, Glickman JF, Steegborn C, Levin LR, and Buck J
- Subjects
- Adenylyl Cyclase Inhibitors chemistry, Adenylyl Cyclases chemistry, Allosteric Regulation drug effects, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Pyrimidines chemistry, Solubility, Structure-Activity Relationship, Thiophenes chemistry, Adenylyl Cyclase Inhibitors pharmacology, Adenylyl Cyclases metabolism, Pyrimidines pharmacology, Thiophenes pharmacology
- Abstract
The prototypical second messenger cAMP regulates a wide variety of physiological processes. It can simultaneously mediate diverse functions by acting locally in independently regulated microdomains. In mammalian cells, two types of adenylyl cyclase generate cAMP: G-protein-regulated transmembrane adenylyl cyclases and bicarbonate-, calcium- and ATP-regulated soluble adenylyl cyclase (sAC). Because each type of cyclase regulates distinct microdomains, methods to distinguish between them are needed to understand cAMP signaling. We developed a mass-spectrometry-based adenylyl cyclase assay, which we used to identify a new sAC-specific inhibitor, LRE1. LRE1 bound to the bicarbonate activator binding site and inhibited sAC via a unique allosteric mechanism. LRE1 prevented sAC-dependent processes in cellular and physiological systems, and it will facilitate exploration of the therapeutic potential of sAC inhibition., Competing Interests: Drs. Buck, Levin and Zippin own equity interest in CEP Biotech which has licensed commercialization of a panel of monoclonal antibodies directed against sAC. All other authors declare that they have no conflicts of interest with the contents of this article.
- Published
- 2016
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