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Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
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; Glickman, J Fraser; Steegborn, Clemens; Levin, Lonny R; Buck, Jochen.
Affiliation
  • Ramos-Espiritu L; Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
  • Kleinboelting S; The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
  • Navarrete FA; Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
  • Alvau A; Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
  • Visconti PE; Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
  • Valsecchi F; Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
  • Starkov A; Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
  • Manfredi G; Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
  • Buck H; Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
  • Adura C; Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
  • Zippin JH; The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
  • van den Heuvel J; Department of Dermatology, Weill Cornell Medical College, New York, New York, USA.
  • Glickman JF; Helmholtz Zentrum fur Infektionsforschung, Braunschweig, Germany.
  • Steegborn C; The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
  • Levin LR; Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
  • Buck J; Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
Nat Chem Biol ; 12(10): 838-44, 2016 10.
Article in En | MEDLINE | ID: mdl-27547922
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.
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Full text: 1 Database: MEDLINE Main subject: Pyrimidines / Thiophenes / Adenylyl Cyclases / Adenylyl Cyclase Inhibitors Limits: Humans Language: En Year: 2016 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Pyrimidines / Thiophenes / Adenylyl Cyclases / Adenylyl Cyclase Inhibitors Limits: Humans Language: En Year: 2016 Type: Article