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==Overview== | ==Overview== | ||
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. | 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. | ||
==Disease== | |||
Known diseases associated with this structure: Breast and colorectal cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604373 604373]], Breast cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604373 604373]], Li-Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604373 604373]], Osteosarcoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604373 604373]], Prostate cancer, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604373 604373]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:16:29 2007'' | ||