2I67

Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis

2I67 の概要

• エントリーDOI: 10.2210/pdb2i67/pdb
• 関連するPDBエントリー: 2I65 2I66
• 分子名称: ADP-ribosyl cyclase 1, ADENOSINE-5-DIPHOSPHORIBOSE (3 entities in total)
• 機能のキーワード: the catalytic pocket, reaction product, reaction intermediate, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type II membrane protein: P28907
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62438.73

構造登録者

Liu, Q.,Kriksunov, I.A.,Graeff, R.,Munshi, C.,Lee, H.C.,Hao, Q. (登録日: 2006-08-28, 公開日: 2006-09-05, 最終更新日: 2024-10-30)

主引用文献

Liu, Q.,Kriksunov, I.A.,Graeff, R.,Munshi, C.,Lee, H.C.,Hao, Q.
Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis.
J.Biol.Chem., 281:32861-32869, 2006

PubMed Abstract: The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD(+)) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD(+) to synthesize two calcium-mobilizing molecules. By using NAD(+) and a surrogate substrate, NGD(+), we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu(226) rather than by a covalent linkage. The polar interactions between Glu(226) and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser(193) was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.

PubMed: 16951430
DOI: 10.1074/jbc.M606365200

実験手法

X-RAY DIFFRACTION (1.71 Å)