2ckp: Difference between revisions
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==Overview== | ==Overview== | ||
Choline kinase, responsible for the phosphorylation of choline to | 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== | ==Disease== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
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Revision as of 17:49, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN CHOLINE KINASE ALPHA-2 IN COMPLEX WITH ADP
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Breast and colorectal cancer, susceptibility to OMIM:[604373], Breast cancer, susceptibility to OMIM:[604373], Li-Fraumeni syndrome OMIM:[604373], Osteosarcoma, somatic OMIM:[604373], Prostate cancer, familial OMIM:[604373]
About this StructureAbout this Structure
2CKP is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Choline kinase, with EC number 2.7.1.32 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Elucidation of human choline kinase crystal structures in complex with the products ADP or phosphocholine., Malito E, Sekulic N, Too WC, Konrad M, Lavie A, J Mol Biol. 2006 Nov 24;364(2):136-51. Epub 2006 Sep 3. PMID:17007874
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