Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine

[摘要] 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.

[发布日期] 2006-11-24

[关键词] choline kinase;phosphoryl transfer;crystal structure