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

Nature chemical biology 2016 Oct

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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.

Citation

Lavoisier Ramos-Espiritu, Silke Kleinboelting, Felipe A Navarrete, Antonio Alvau, Pablo E Visconti, Federica Valsecchi, Anatoly Starkov, Giovanni Manfredi, Hannes Buck, Carolina Adura, Jonathan H Zippin, Joop van den Heuvel, J Fraser Glickman, Clemens Steegborn, Lonny R Levin, Jochen Buck. Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nature chemical biology. 2016 Oct;12(10):838-44