PDBsum entry 5iv4

Lyase

PDB id: 5iv4

Contents

Protein chain

461 a.a.

Ligands

LRI

ACT ×2

EDO ×5

DMS ×4

PEG

GOL

Metals

_CL

Waters ×358

References listed in PDB file

Key reference

• Title: Discovery of lre1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
• Authors: L.Ramos-Espiritu, S.Kleinboelting, F.A.Navarrete, A.Alvau, P.E.Visconti, F.Valsecchi, A.Starkov, G.Manfredi, H.Buck, C.Adura, J.H.Zippin, J.Van den heuvel, J.F.Glickman, C.Steegborn, L.R.Levin, J.Buck.
• Ref.: Nat Chem Biol, 2016, 12, 838-844. [DOI no: 10.1038/nchembio.2151]
• PubMed id: 27547922

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.