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首页> 外文期刊>Journal of Molecular Biology >Crystallographic analysis of the reaction cycle of 2′,3′-cyclic nucleotide 3′-phosphodiesterase, a unique member of the 2H phosphoesterase family
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Crystallographic analysis of the reaction cycle of 2′,3′-cyclic nucleotide 3′-phosphodiesterase, a unique member of the 2H phosphoesterase family

机译：2'，3'-环核苷酸3'-磷酸二酯酶（2H磷酸酯酶家族的独特成员）的反应周期的晶体学分析

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摘要

2H phosphoesterases catalyze reactions on nucleotide substrates and contain two conserved histidine residues in the active site. Very limited information is currently available on the details of the active site and substrate/product binding during the catalytic cycle of these enzymes. We performed a comprehensive X-ray crystallographic study of mouse 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), a membrane-associated enzyme present at high levels in the tetrapod myelin sheath. We determined crystal structures of the CNPase phosphodiesterase domain complexed with substrate, product, and phosphorothioate analogues. The data provide detailed information on the CNPase reaction mechanism, including substrate binding mode and coordination of the nucleophilic water molecule. Linked to the reaction, an open/close motion of the β5-α7 loop is observed. The role of the N terminus of helix α7 - unique for CNPase in the 2H family - during the reaction indicates that 2H phosphoesterases differ in their respective reaction mechanisms despite the conserved catalytic residues. Furthermore, based on small-angle X-ray scattering, we present a model for the full-length enzyme, indicating that the two domains of CNPase form an elongated molecule. Finally, based on our structural data and a comprehensive bioinformatics study, we discuss the conservation of CNPase in various organisms.
机译：2H磷酸酯酶催化核苷酸底物上的反应，并在活性位点包含两个保守的组氨酸残基。当前在这些酶的催化循环期间关于活性位点和底物/产物结合的细节的信息非常有限。我们对小鼠2'，3'-环核苷酸3'-磷酸二酯酶（CNPase）（一种在四足动物髓鞘中高水平存在的膜相关酶）进行了全面的X射线晶体学研究。我们确定了与底物，产物和硫代磷酸酯类似物复合的CNPase磷酸二酯酶结构域的晶体结构。数据提供了有关CNPase反应机理的详细信息，包括底物结合模式和亲核水分子的配位。与该反应有关，观察到了β5-α7环的开/关运动。在反应过程中，对于2P家族中的CNPase而言，螺旋α7的N末端N端的作用表明，尽管保守的催化残基，2H磷酸酯酶在各自的反应机理上也有所不同。此外，基于小角度X射线散射，我们提出了一种全长酶的模型，表明CNPase的两个结构域形成了一个细长分子。最后，基于我们的结构数据和全面的生物信息学研究，我们讨论了CNPase在各种生物中的保守性。

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