4L02

Crystal Structure of SphK1 with inhibitor

Summary for 4L02

• Entry DOI: 10.2210/pdb4l02/pdb
• Related: 3VZB 3VZC 3VZD
• Descriptor: 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)
• Functional Keywords: lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9NYA1
• Total number of polymer chains: 3
• Total formula weight: 130110.18

Authors

Min, X.,Walker, N.,Wang, Z. (deposition date: 2013-05-30, release date: 2013-07-24, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.75 Å)