4CLZ

Crystal structure of human soluble Adenylyl Cyclase with Inhibitor 4, 4'-Diisothiocyano-2,2'-stilbenedisulfonic acid

4CLZ の概要

• エントリーDOI: 10.2210/pdb4clz/pdb
• 関連するPDBエントリー: 4CLF 4CLK 4CLL 4CLP 4CLS 4CLT 4CLU 4CLW 4CLY 4CM0 4CM2
• 分子名称: ADENYLATE CYCLASE TYPE 10, ACETATE ION, 1,2-ETHANEDIOL, ... (7 entities in total)
• 機能のキーワード: lyase, nucleotide-binding
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56530.23

構造登録者

Kleinboelting, S.,Weyand, M.,Steegborn, C. (登録日: 2014-01-15, 公開日: 2014-03-05, 最終更新日: 2024-10-23)

主引用文献

Kleinboelting, S.,Diaz, A.,Moniot, S.,Van Den Heuvel, J.,Weyand, M.,Levin, L.R.,Buck, J.,Steegborn, C.
Crystal Structures of Human Soluble Adenylyl Cyclase Reveal Mechanisms of Catalysis and of its Activation Through Bicarbonate.
Proc.Natl.Acad.Sci.USA, 111:3727-, 2014

PubMed Abstract: cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3(-)); it thereby serves as a cellular sensor for HCO3(-), carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3(-) binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3(-) activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3(-) sensing and a basis for targeting this system with drugs.

PubMed: 24567411
DOI: 10.1073/PNAS.1322778111

実験手法

X-RAY DIFFRACTION (1.9 Å)