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PDBsum entry 3vzc
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Transferase/inhibitor
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PDB id
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3vzc
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References listed in PDB file
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Key reference
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Title
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Molecular basis of sphingosine kinase 1 substrate recognition and catalysis.
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Authors
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Z.Wang,
X.Min,
S.H.Xiao,
S.Johnstone,
W.Romanow,
D.Meininger,
H.Xu,
J.Liu,
J.Dai,
S.An,
S.Thibault,
N.Walker.
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Ref.
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Structure, 2013,
21,
798-809.
[DOI no: ]
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PubMed id
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Abstract
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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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