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Structure. 2013 May 7;21(5):798-809. doi: 10.1016/j.str.2013.02.025. Epub 2013 Apr 18.

Molecular basis of sphingosine kinase 1 substrate recognition and catalysis.

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1
Department of Molecular Structure and Characterization, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. zwang@amgen.com

Abstract

Sphingosine kinase 1 (SphK1) is a lipid kinase that catalyzes the conversion of sphingosine to sphingosine-1-phosphate (S1P), which has been shown to play a role in lymphocyte trafficking, angiogenesis, and response to apoptotic stimuli. As a central enzyme in modulating the S1P levels in cells, SphK1 emerges as an important regulator for diverse cellular functions and a potential target for drug discovery. Here, we present the crystal structures of human SphK1 in the apo form and in complexes with a substrate sphingosine-like lipid, ADP, and an inhibitor at 2.0-2.3 Å resolution. The SphK1 structures reveal a two-domain architecture in which its catalytic site is located in the cleft between the two domains and a hydrophobic lipid-binding pocket is buried in the C-terminal domain. Comparative analysis of these structures with mutagenesis and kinetic studies provides insight into how SphK1 recognizes the lipid substrate and catalyzes ATP-dependent phosphorylation.

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PMID:
23602659
DOI:
10.1016/j.str.2013.02.025
[Indexed for MEDLINE]
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