Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities
Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities
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DOI：
10.1006/jmbi.2001.5386
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发表时间：
2002-02-22
影响因子：
5.6
通讯作者：
Morikawa, K
中科院分区：
文献类型：
--
作者：
Yamamoto-Katayama, S;Ariyoshi, M;Morikawa, K
cADPR是一种新的第二信使，它促进细胞内钙库的钙释放，其作用不依赖于IP 3。在哺乳动物中，ADP-核糖基环化酶的功能存在于两种膜蛋白中，即CD 38和BST-1/CD 157。这些酶暴露于细胞外，具有cADPR水解酶和NAD糖水解酶活性。尽管其功能的重要性，这些酶促反应的结构基础仍然难以捉摸。我们以原子分辨率确定了游离形式和与5种底物类似物（烟酰胺、NMN、ATP γ S、ethenoNADP和ethenoNAD）复合的人BST-1胞外区的晶体结构。这些配体的反应中心的三维结构视图揭示了底物结合的模式和多功能酶促反应的催化机制。在二聚酶的每个催化裂缝中，底物主要通过与两个色氨酸残基的货车范德华相互作用来识别，从而NAD的N-糖苷键正确地暴露在催化谷氨酸残基附近。其羧基侧链稳定SO型反应的催化中间体。催化裂的这种构象也暗示了腺嘌呤碱基和核糖之间的环化机制。这三个关键残基在BST-1、CD 38和Aaplasia环化酶的序列中是不变的，因此这种底物识别模式和催化方案似乎在环化酶家族中是常见的。(C)2002年爱思唯尔科学有限公司
cADPR is the novel second messenger that elicits calcium release from intracellular calcium stores and works independently Of IP3. In mammals, the ADP-ribosyl cyclase function is found in two membrane proteins, CD38 and BST-1/CD157. These enzymes, exposed extracellularly, bear cADPR hydrolase and NAD glycohydrolase activities. In spite of its functional importance, the structural basis of these enzymatic reactions remains elusive. We determined the crystal structures of the extracellular region of human BST-1 at atomic resolution in the free form and in complexes with five substrate analogues: nicotinamide, NMN, ATPgammaS, ethenoNADP, and ethenoNAD. The three-dimensional structural views of the reaction centre with these ligands revealed the mode of substrate binding and the catalytic mechanism of the multifunctional enzymatic reactions. In each catalytic cleft of the dimeric enzyme, substrates are recognized predominantly through van der Waals interactions with two tryptophan residues, and thereby the N-glycosidic bond of NAD is correctly exposed near a catalytic glutamate residue. Its carboxyl side-chain stabilizes the catalytic intermediate of the SO type reaction. This conformation of the catalytic cleft also implies the mechanism of cyclization between the adenine base and the ribose. The three key residues are invariant among the sequences of BST-1, CD38, and Aplysia cyclase, and hence this substrate recognition mode and catalytic scheme appear to be common in the cyclase family. (C) 2002 Elsevier Science Ltd.