5IV3

Crystal structure of human soluble adenylyl cyclase in complex with alpha,beta-methyleneadenosine-5'-triphosphate and the allosteric inhibitor LRE1

Summary for 5IV3

• Entry DOI: 10.2210/pdb5iv3/pdb
• Descriptor: Adenylate cyclase type 10, ACETATE ION, GLYCEROL, ... (10 entities in total)
• Functional Keywords: human soluble adenylyl cyclase hsac complex alpha, beta-methyleneadenosine-5'-triphosphate, allosteric inhibitor lre1, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : Q96PN6
• Total number of polymer chains: 1
• Total formula weight: 55693.74

Authors

Kleinboelting, S.,Steegborn, C. (deposition date: 2016-03-18, release date: 2016-08-17, Last modification date: 2024-01-10)

Primary citation

Ramos-Espiritu, L.,Kleinboelting, S.,Navarrete, F.A.,Alvau, A.,Visconti, P.E.,Valsecchi, F.,Starkov, A.,Manfredi, G.,Buck, H.,Adura, C.,Zippin, J.H.,van den Heuvel, J.,Glickman, J.F.,Steegborn, C.,Levin, L.R.,Buck, J.
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
Nat.Chem.Biol., 12:838-844, 2016

PubMed 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.

PubMed: 27547922
DOI: 10.1038/nchembio.2151

Experimental method

X-RAY DIFFRACTION (1.86 Å)