4L02

Crystal Structure of SphK1 with inhibitor

4L02 の概要

• エントリーDOI: 10.2210/pdb4l02/pdb
• 関連するPDBエントリー: 3VZB 3VZC 3VZD
• 分子名称: Sphingosine kinase 1, (2R,4S)-1-[2-(4-{[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-2-(hydroxymethyl)piperidin-4-ol (3 entities in total)
• 機能のキーワード: lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9NYA1
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 130110.18

構造登録者

Min, X.,Walker, N.,Wang, Z. (登録日: 2013-05-30, 公開日: 2013-07-24, 最終更新日: 2024-02-28)

主引用文献

Gustin, D.J.,Li, Y.,Brown, M.L.,Min, X.,Schmitt, M.J.,Wanska, M.,Wang, X.,Connors, R.,Johnstone, S.,Cardozo, M.,Cheng, A.C.,Jeffries, S.,Franks, B.,Li, S.,Shen, S.,Wong, M.,Wesche, H.,Xu, G.,Carlson, T.J.,Plant, M.,Morgenstern, K.,Rex, K.,Schmitt, J.,Coxon, A.,Walker, N.,Kayser, F.,Wang, Z.
Structure guided design of a series of sphingosine kinase (SphK) inhibitors.
Bioorg.Med.Chem.Lett., 23:4608-4616, 2013

PubMed Abstract: Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.

PubMed: 23845219
DOI: 10.1016/j.bmcl.2013.06.030

実験手法

X-RAY DIFFRACTION (2.75 Å)