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Ramos-Espiritu, Lavoisier ; Kleinbölting, 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:
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
In: Nature Chemical Biology.
Bd. 12
(2016)
.
- S. 838-844.
ISSN 1552-4469
DOI: https://doi.org/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.