Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase Academic Article uri icon

Overview

MeSH Major

  • Adenylyl Cyclase Inhibitors
  • Adenylyl Cyclases
  • Pyrimidines
  • Thiophenes

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.

publication date

  • October 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5030147

Digital Object Identifier (DOI)

  • 10.1038/nchembio.2151

PubMed ID

  • 27547922

Additional Document Info

start page

  • 838

end page

  • 44

volume

  • 12

number

  • 10