5IV4
Crystal structure of the human soluble adenylyl cyclase in complex with the allosteric inhibitor LRE1
Summary for 5IV4
| Entry DOI | 10.2210/pdb5iv4/pdb |
| Descriptor | Adenylate cyclase type 10, 6-chloro-N~4~-cyclopropyl-N~4~-[(thiophen-2-yl)methyl]pyrimidine-2,4-diamine, ACETATE ION, ... (9 entities in total) |
| Functional Keywords | human soluble adenylyl cyclase complex lre1 inhibitor, 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 | 55525.07 |
| Authors | Kleinboelting, S.,Steegborn, C. (deposition date: 2016-03-18, release date: 2016-08-17, Last modification date: 2024-11-20) |
| 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 Cited by 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: 27547922DOI: 10.1038/nchembio.2151 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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