title: Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.|The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
authors.forename: Lavoisier
authors.initials: L
authors.lastname: Ramos-Espiritu
authors.affiliation: Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kleinboelting
authors.affiliation: Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Navarrete
authors.affiliation: Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alvau
authors.affiliation: Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Visconti
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Valsecchi
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Starkov
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Buck
authors.affiliation: The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Adura
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Zippin
authors.affiliation: Helmholtz Zentrum fur Infektionsforschung, Braunschweig, Germany.
authors.forename: Joop
authors.identifier: 0000-0001-5085-4010
authors.initials: J
authors.lastname: van den Heuvel
authors.affiliation: The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
authors.forename: J Fraser
authors.identifier: 0000-0002-6706-4039
authors.initials: JF
authors.lastname: Glickman
authors.affiliation: Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Lonny R
authors.identifier: 0000-0002-5204-6356
authors.initials: LR
authors.lastname: Levin
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D011743:Pyrimidines; C000618757:RU-0204277; D013876:Thiophenes; D000262:Adenylyl Cyclases