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Nat Chem Biol. 2016 Oct;12(10):838-44. doi: 10.1038/nchembio.2151. Epub 2016 Aug 22.

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

Author information

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.

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.

PMID:
27547922
PMCID:
PMC5030147
DOI:
10.1038/nchembio.2151
[Indexed for MEDLINE]
Free PMC Article

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