Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
dc.contributor.author | Ramos-Espiritu, Lavoisier | |
dc.contributor.author | Kleinboelting, Silke | |
dc.contributor.author | Navarrete, Felipe A | |
dc.contributor.author | Alvau, Antonio | |
dc.contributor.author | Visconti, Pablo E | |
dc.contributor.author | Valsecchi, Federica | |
dc.contributor.author | Starkov, Anatoly | |
dc.contributor.author | Manfredi, Giovanni | |
dc.contributor.author | Buck, Hannes | |
dc.contributor.author | Adura, Carolina | |
dc.contributor.author | Zippin, Jonathan H | |
dc.contributor.author | van den Heuvel, Joop | |
dc.contributor.author | Glickman, J Fraser | |
dc.contributor.author | Steegborn, Clemens | |
dc.contributor.author | Levin, Lonny R | |
dc.contributor.author | Buck, Jochen | |
dc.date.accessioned | 2018-03-02T15:30:30Z | |
dc.date.available | 2018-03-02T15:30:30Z | |
dc.date.issued | 2016 | |
dc.identifier.citation | Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. 2016, 12 (10):838-44 Nat. Chem. Biol. | en |
dc.identifier.issn | 1552-4469 | |
dc.identifier.pmid | 27547922 | |
dc.identifier.doi | 10.1038/nchembio.2151 | |
dc.identifier.uri | http://hdl.handle.net/10033/621302 | |
dc.description.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. | |
dc.language.iso | en | en |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Adenylyl Cyclase Inhibitors | en |
dc.subject.mesh | Adenylyl Cyclases | en |
dc.subject.mesh | Allosteric Regulation | en |
dc.subject.mesh | Dose-Response Relationship, Drug | en |
dc.subject.mesh | Humans | en |
dc.subject.mesh | Models, Molecular | en |
dc.subject.mesh | Molecular Structure | en |
dc.subject.mesh | Pyrimidines | en |
dc.subject.mesh | Solubility | en |
dc.subject.mesh | Structure-Activity Relationship | en |
dc.subject.mesh | Thiophenes | en |
dc.title | Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. | en |
dc.type | Article | en |
dc.contributor.department | Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. | en |
dc.identifier.journal | Nature chemical biology | en |
refterms.dateFOA | 2018-06-12T22:01:52Z | |
html.description.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. |