(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition.
(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition.
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DOI：
10.1016/j.chembiol.2018.11.001
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发表时间：
2018-12-20
影响因子：
8.6
通讯作者：
Ahel I
中科院分区：
文献类型：
--
作者：
Rack JGM;Ariza A;Drown BS;Henfrey C;Bartlett E;Shirai T;Hergenrother PJ;Ahel I
蛋白质ADP-核糖基化是一种高度动态的翻译后修饰。其中，ADP-（核糖基）水解酶（ARH）是逆转这种修饰的古老酶家族。近年来，ARH由于其作为细胞应激调节因子和肿瘤抑制因子的作用而受到关注。在这里，我们提出了一个全面的结构分析的酶活性家族成员ARH 1和ARH 3。这两种酶具有非常不同的底物需求。我们的数据表明，腺苷核糖部分的结合是高度发散的两种酶之间，而活性位点窝藏远端核糖密切相似。尽管有这种明显的相似性，我们阐明了ADP-核糖类似物ADP-HPD和精氨酸-ADP-核糖选择性抑制ARH 3的结构基础。总之，我们的生物化学和结构工作提供了重要的见解酶-配体相互作用的模式，有助于了解其催化行为的差异，并为靶向药物设计提供了有用的工具。ARH 1和ARH 3具有高度的结构相似性，但不同的配体结合模式结构揭示了观察到的α-1″-连接底物的选择性的原因ARH 3，而不是ARH 1，对产物（类似物）抑制敏感。催化Mg 2+离子的置换导致抑制（例如，通过ADP-HPM或CaCl 2）Rack等人。描述了（ADP-核糖基）水解酶ARH 1和ARH 3的配体和抑制剂键形式的原子分辨率结构。这些结构为这些抑制剂的差异抑制提供了分子基础，并可能有助于阐明ARH 1/3的生理功能。
Protein ADP-ribosylation is a highly dynamic post-translational modification. The rapid turnover is achieved, among others, by ADP-(ribosyl)hydrolases (ARHs), an ancient family of enzymes that reverses this modification. Recently ARHs came into focus due to their role as regulators of cellular stresses and tumor suppressors. Here we present a comprehensive structural analysis of the enzymatically active family members ARH1 and ARH3. These two enzymes have very distinct substrate requirements. Our data show that binding of the adenosine ribose moiety is highly diverged between the two enzymes, whereas the active sites harboring the distal ribose closely resemble each other. Despite this apparent similarity, we elucidate the structural basis for the selective inhibition of ARH3 by the ADP-ribose analogues ADP-HPD and arginine-ADP-ribose. Together, our biochemical and structural work provides important insights into the mode of enzyme-ligand interaction, helps to understand differences in their catalytic behavior, and provides useful tools for targeted drug design. ARH1 and ARH3 have high structural similarity, but different modes of ligand binding Structures unveil reason for the observed selectivity of α-1″-linked substrates ARH3, but not ARH1, is susceptible to product (analogue) inhibition Displacement of a catalytic Mg2+ ion leads to inhibition (e.g., by ADP-HPM or CaCl2) Rack et al. describe the atomic resolution structures of the (ADP-ribosyl)hydrolases ARH1 and ARH3 in their ligand and inhibitor bond forms. The structures provide a molecular basis for their differential inhibition by these inhibitors and may aid ongoing efforts to elucidate the physiological function of ARH1/3.
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DOI：
10.1093/bioinformatics/btq224
发表时间：
2010-08-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Katoh K;Toh H
通讯作者：
Toh H
影响因子：
15
作者：
Lambrecht MJ;Brichacek M;Barkauskaite E;Ariza A;Ahel I;Hergenrother PJ
通讯作者：
Hergenrother PJ
影响因子：
3.8
作者：
Gravells P;Grant E;Smith KM;James DI;Bryant HE
通讯作者：
Bryant HE
影响因子：
5.3
作者：
Kato, Jiro;Zhu, Jianfeng;Moss, Joel
通讯作者：
Moss, Joel
影响因子：
16
作者：
Gibbs-Seymour I;Fontana P;Rack JGM;Ahel I
通讯作者：
Ahel I