Structural highlights
3g15 is a 2 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 3f2s. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , |
| Related: | 3f2s |
| Gene: | CHKA, CHK, CKI (HUMAN) |
| Activity: | Choline kinase, with EC number 2.7.1.32 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CHKA_HUMAN] Has a key role in phospholipid biosynthesis and may contribute to tumor cell growth. Catalyzes the first step in phosphatidylcholine biosynthesis. Contributes to phosphatidylethanolamine biosynthesis. Phosphorylates choline and ethanolamine. Has higher activity with choline.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoKalpha (alpha1 and alpha2) and ChoKbeta isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoKalpha1 and ChoKbeta isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoKalpha1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoKbeta was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoKalpha isoforms (alpha1 and alpha2) compared with ChoKbeta. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoKalpha2 (equivalent to Leu-419 of ChoKalpha1), or the corresponding residue Phe-352 of ChoKbeta, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.
Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity.,Hong BS, Allali-Hassani A, Tempel W, Finerty PJ Jr, Mackenzie F, Dimov S, Vedadi M, Park HW J Biol Chem. 2010 May 21;285(21):16330-40. Epub 2010 Mar 18. PMID:20299452[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gallego-Ortega D, Ramirez de Molina A, Ramos MA, Valdes-Mora F, Barderas MG, Sarmentero-Estrada J, Lacal JC. Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment. PLoS One. 2009 Nov 12;4(11):e7819. doi: 10.1371/journal.pone.0007819. PMID:19915674 doi:10.1371/journal.pone.0007819
- ↑ Hong BS, Allali-Hassani A, Tempel W, Finerty PJ Jr, Mackenzie F, Dimov S, Vedadi M, Park HW. Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity. J Biol Chem. 2010 May 21;285(21):16330-40. Epub 2010 Mar 18. PMID:20299452 doi:10.1074/jbc.M109.039024
