3ROQ

Crystal structure of human CD38 in complex with compound CZ-46

3ROQ の概要

• エントリーDOI: 10.2210/pdb3roq/pdb
• 関連するPDBエントリー: 1YH3 3ROK 3ROM 3ROP
• 分子名称: ADP-ribosyl cyclase 1, (2R,3R,4S,5S)-4-fluoro-3,5-dihydroxytetrahydrofuran-2-yl 2-phenylethyl hydrogen (S)-phosphate (3 entities in total)
• 機能のキーワード: cd38, adp-ribosyl cyclase, cyclic adp-ribose, calcium signaling, inhibitory compound, covalent intermediate, cz-46, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59723.40

構造登録者

Zhang, H.,Lee, H.C.,Hao, Q. (登録日: 2011-04-26, 公開日: 2011-12-21, 最終更新日: 2024-10-30)

主引用文献

Kwong, A.K.,Chen, Z.,Zhang, H.,Leung, F.P.,Lam, C.M.,Ting, K.Y.,Zhang, L.,Hao, Q.,Zhang, L.H.,Lee, H.C.
Catalysis-based inhibitors of the calcium signaling function of CD38.
Biochemistry, 51:555-564, 2012

PubMed Abstract: CD38 is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate; both are universal Ca(2+) messenger molecules. Ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior. A series of catalysis-based inhibitors of CD38 were designed and synthesized, starting with arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide. Structure-function relationships were analyzed to assess the structural determinants important for inhibiting the NADase activity of CD38. X-ray crystallography was used to reveal the covalent intermediates that were formed with the catalytic residue, Glu226. Metabolically stable analogues that were resistant to inactivation by phosphatase and esterase were synthesized and shown to be effective in inhibiting intracellular cADPR production in human HL-60 cells during induction of differentiation by retinoic acid. The inhibition was species-independent, and the analogues were similarly effective in blocking the cyclization reaction of CD38 in rat ventricular tissue extracts, as well as inhibiting the α-agonist-induced constriction in rat mesentery arteries. These compounds thus represent the first generally applicable and catalysis-based inhibitors of the Ca(2+) signaling function of CD38.

PubMed: 22142305
DOI: 10.1021/bi201509f

実験手法

X-RAY DIFFRACTION (2.1 Å)