Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine |
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Authors: | Malito Enrico Sekulic Nikolina Too Wei Cun See Konrad Manfred Lavie Arnon |
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Affiliation: | Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA. |
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Abstract: | Choline kinase, responsible for the phosphorylation of choline to phosphocholine as the first step of the CDP-choline pathway for the biosynthesis of phosphatidylcholine, 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 molecular details of the substrate binding sites. ATP binds in a cavity where residues from both the N and C-terminal lobes contribute to form a cleft, while the choline-binding site constitutes a deep hydrophobic groove 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. |
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Keywords: | CK, choline kinase hCK, human CK PChol, phosphocholine PtdCho, phosphatidylcholine hCKα2, human choline kinase isoform α2 ePK, eukaryotic protein kinase APHs, aminoglycoside phosphotransferases |
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