3LQ3: Crystal structure of human choline kinase beta in complex with phosphorylated hemicholinium-3 and adenosine nucleotide

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.
PDB ID: 3LQ3Download
MMDB ID: 81879
PDB Deposition Date: 2010/2/8
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.42  Å
Source Organism:
Similar Structures:
Biological Unit for 3LQ3: dimeric; determined by software (PISA)
Molecular Components in 3LQ3
Label Count Molecule
Proteins (2 molecules)
Choline/ethanolamine Kinase(Gene symbol: CHKB)
Molecule annotation
Chemicals (14 molecules)
Molecule information is not avaliable.
* Click molecule labels to explore molecular sequence information.

Citing MMDB