Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine
Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine
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DOI：
10.1016/j.jmb.2006.08.084
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发表时间：
2006-11-24
影响因子：
5.6
通讯作者：
Lavie, Arnon
中科院分区：
文献类型：
--
作者：
Malito, Enrico;Sekulic, Nikolina;Lavie, Arnon
胆碱激酶负责将胆碱磷酸化为磷酸胆碱，作为磷脂酰胆碱生物合成的CDP-胆碱途径的第一步，已被认为是抗癌治疗的新靶点。人胆碱激酶在其 apo、ADP 和磷酸胆碱结合复合物中的晶体结构分别揭示了来自 N 和 C 端叶的残基在 C 端结构域中形成具有由带负电残基组成的边缘的位置。与胆碱结合后，酶会发生构象变化，独立影响 N 末端结构域和 ATP 结合环。根据这种结构分析和与其他激酶的比较，以及同源秀丽隐杆线虫胆碱激酶的诱变数据，建立了三元 ADP-磷酸胆碱复合物模型，揭示了该酶磷酰基转移活性的分子基础。 (c) 2006 Elsevier Ltd. 保留所有权利。
Choline kinase, responsible for the phosphorylation of choline to phosphocholine as the first step of the CDP-choline pathway for the biosynthesis of phosphatidylchohine, has been recognized as a new target for anticancer therapy. Crystal structures of human choline kinase in its apo, ADP and phosphocholine-bound complexes, respectively, reveal the where residues from both the N and C-terminal lobes contribute to form a in the C-terminal domain with a rim composed of negatively charged residues. Upon binding of choline, the enzyme undergoes conformational changes independently affecting the N-terminal domain and the ATP-binding loop. From this structural analysis and comparison with other kinases, and from mutagenesis data on the homologous Caenorhabditis elegans choline kinase, a model of the ternary ADP-phosphocholine complex was built that reveals the molecular basis for the phosphoryl transfer activity of this enzyme. (c) 2006 Elsevier Ltd. All rights reserved.