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3G15

Crystal structure of human choline kinase alpha in complex with hemicholinium-3 and ADP

3F2S」から置き換えられました
3G15 の概要
エントリーDOI10.2210/pdb3g15/pdb
関連するPDBエントリー3F2S
分子名称Choline kinase alpha, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total)
機能のキーワードnon-protein kinase, choline kinase, structural genomics consortium, sgc, hemicholinium-3, kinase, transferase
由来する生物種Homo sapiens (human)
タンパク質・核酸の鎖数2
化学式量合計95685.78
構造登録者
主引用文献Hong, B.S.,Allali-Hassani, A.,Tempel, W.,Finerty, P.J.,Mackenzie, F.,Dimov, S.,Vedadi, M.,Park, H.W.
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., 285:16330-16340, 2010
Cited by
PubMed Abstract: 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.
PubMed: 20299452
DOI: 10.1074/jbc.M109.039024
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.7 Å)
構造検証レポート
Validation report summary of 3g15
検証レポート(詳細版)ダウンロードをダウンロード

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件を2024-11-06に公開中

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