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
  • 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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