title: Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Malito
authors.forename: Nikolina
authors.initials: N
authors.lastname: Sekulic
authors.forename: Wei Cun See
authors.initials: WC
authors.lastname: Too
authors.forename: Manfred
authors.initials: M
authors.lastname: Konrad
authors.forename: Arnon
authors.initials: A
authors.lastname: Lavie
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry; D002794:Choline / Q000737:chemistry*; D002797:Choline Kinase / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010767:Phosphorylcholine / Q000737:chemistry*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D029742:Caenorhabditis elegans Proteins; D010767:Phosphorylcholine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002797:Choline Kinase; D002794:Choline