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. Epub 2016 Aug 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclase Inhibitors / chemistry
  • Adenylyl Cyclase Inhibitors / pharmacology*
  • Adenylyl Cyclases / chemistry
  • Adenylyl Cyclases / metabolism*
  • Allosteric Regulation / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*


  • Adenylyl Cyclase Inhibitors
  • Pyrimidines
  • RU-0204277
  • Thiophenes
  • Adenylyl Cyclases

Associated data

  • PubChem-Substance/315661370
  • PubChem-Substance/315661371