5IV4

Crystal structure of the human soluble adenylyl cyclase in complex with the allosteric inhibitor LRE1

5IV4 の概要

• エントリーDOI: 10.2210/pdb5iv4/pdb
• 分子名称: 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)
• 機能のキーワード: human soluble adenylyl cyclase complex lre1 inhibitor, lyase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : Q96PN6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55525.07

構造登録者

Kleinboelting, S.,Steegborn, C. (登録日: 2016-03-18, 公開日: 2016-08-17, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.79 Å)