Crystal Structure of Sphingosine Kinase 1 with PF-543

Jing Wang; Stefan Knapp; Nigel J Pyne; Susan Pyne; Jonathan M Elkins

doi:10.1021/ml5004074

Crystal Structure of Sphingosine Kinase 1 with PF-543

ACS Med Chem Lett. 2014 Oct 27;5(12):1329-33. doi: 10.1021/ml5004074. eCollection 2014 Dec 11.

Authors

Jing Wang¹, Stefan Knapp², Nigel J Pyne³, Susan Pyne³, Jonathan M Elkins¹

Affiliations

¹ Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
² Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K. ; Target Discovery Institute, University of Oxford , NDM Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, U.K.
³ Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , Glasgow G4 0RE, U.K.

Abstract

The most potent inhibitor of Sphingosine Kinase 1 (SPHK1) so far identified is PF-543. The crystal structure of SPHK1 in complex with inhibitor PF-543 to 1.8 Å resolution reveals the inhibitor bound in a bent conformation analogous to that expected of a bound sphingosine substrate but with a rotated head group. The structural data presented will aid in the design of SPHK1 and SPHK2 inhibitors with improved properties.

Keywords: PF-543; S1P; SPHK1; SPHK2; lipid; sphingosine.

Grants and funding

092809/Wellcome Trust/United Kingdom