2. Academic Validation
  3. Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase

Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase

  • Nat Chem Biol. 2016 Oct;12(10):838-44. doi: 10.1038/nchembio.2151.
Lavoisier Ramos-Espiritu 1 2,  Silke Kleinboelting 3,  Felipe A Navarrete 4,  Antonio Alvau 4,  Pablo E Visconti 4,  Federica Valsecchi 5,  Anatoly Starkov 5,  Giovanni Manfredi 5,  Hannes Buck 1,  Carolina Adura 2,  Jonathan H Zippin 6,  Joop van den Heuvel 7,  J Fraser Glickman 2,  Clemens Steegborn 3,  Lonny R Levin 1,  Jochen Buck 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
  • 2 The High-Throughput Screening and Spectroscopy Resource Center, The Rockefeller University, New York, New York, USA.
  • 3 Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
  • 4 Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts, USA.
  • 5 Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA.
  • 6 Department of Dermatology, Weill Cornell Medical College, New York, New York, USA.
  • 7 Helmholtz Zentrum fur Infektionsforschung, Braunschweig, Germany.
PMID: 27547922 DOI: 10.1038/nchembio.2151
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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