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dc.contributor.authorRamos-Espiritu, Lavoisier
dc.contributor.authorKleinboelting, Silke
dc.contributor.authorNavarrete, Felipe A
dc.contributor.authorAlvau, Antonio
dc.contributor.authorVisconti, Pablo E
dc.contributor.authorValsecchi, Federica
dc.contributor.authorStarkov, Anatoly
dc.contributor.authorManfredi, Giovanni
dc.contributor.authorBuck, Hannes
dc.contributor.authorAdura, Carolina
dc.contributor.authorZippin, Jonathan H
dc.contributor.authorvan den Heuvel, Joop
dc.contributor.authorGlickman, J Fraser
dc.contributor.authorSteegborn, Clemens
dc.contributor.authorLevin, Lonny R
dc.contributor.authorBuck, Jochen
dc.date.accessioned2018-03-02T15:30:30Z
dc.date.available2018-03-02T15:30:30Z
dc.date.issued2016
dc.identifier.citationDiscovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. 2016, 12 (10):838-44 Nat. Chem. Biol.en
dc.identifier.issn1552-4469
dc.identifier.pmid27547922
dc.identifier.doi10.1038/nchembio.2151
dc.identifier.urihttp://hdl.handle.net/10033/621302
dc.description.abstractThe 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.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdenylyl Cyclase Inhibitorsen
dc.subject.meshAdenylyl Cyclasesen
dc.subject.meshAllosteric Regulationen
dc.subject.meshDose-Response Relationship, Drugen
dc.subject.meshHumansen
dc.subject.meshModels, Molecularen
dc.subject.meshMolecular Structureen
dc.subject.meshPyrimidinesen
dc.subject.meshSolubilityen
dc.subject.meshStructure-Activity Relationshipen
dc.subject.meshThiophenesen
dc.titleDiscovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalNature chemical biologyen
refterms.dateFOA2018-06-12T22:01:52Z
html.description.abstractThe 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.


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