2.50
Hdl Handle:
http://hdl.handle.net/10033/621302
Title:
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
Authors:
Ramos-Espiritu, Lavoisier; Kleinboelting, Silke; Navarrete, Felipe A; Alvau, Antonio; Visconti, Pablo E; Valsecchi, Federica; Starkov, Anatoly; Manfredi, Giovanni; Buck, Hannes; Adura, Carolina; Zippin, Jonathan H; van den Heuvel, Joop ( 0000-0001-5085-4010 ) ; Glickman, J Fraser; Steegborn, Clemens; Levin, Lonny R; Buck, Jochen
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.
Affiliation:
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. 2016, 12 (10):838-44 Nat. Chem. Biol.
Journal:
Nature chemical biology
Issue Date:
2016
URI:
http://hdl.handle.net/10033/621302
DOI:
10.1038/nchembio.2151
PubMed ID:
27547922
Type:
Article
Language:
en
ISSN:
1552-4469
Appears in Collections:
publications of the research group recombinant protein expression (RPEX)

Full metadata record

DC FieldValue Language
dc.contributor.authorRamos-Espiritu, Lavoisieren
dc.contributor.authorKleinboelting, Silkeen
dc.contributor.authorNavarrete, Felipe Aen
dc.contributor.authorAlvau, Antonioen
dc.contributor.authorVisconti, Pablo Een
dc.contributor.authorValsecchi, Federicaen
dc.contributor.authorStarkov, Anatolyen
dc.contributor.authorManfredi, Giovannien
dc.contributor.authorBuck, Hannesen
dc.contributor.authorAdura, Carolinaen
dc.contributor.authorZippin, Jonathan Hen
dc.contributor.authorvan den Heuvel, Joopen
dc.contributor.authorGlickman, J Fraseren
dc.contributor.authorSteegborn, Clemensen
dc.contributor.authorLevin, Lonny Ren
dc.contributor.authorBuck, Jochenen
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.en
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

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