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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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PDB id:
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| Name: |
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Transferase/inhibitor
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Title:
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Crystal structure of sphingosine kinase 1 with inhibitor
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Structure:
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Sphingosine kinase 1. Chain: a, b, c, d, e, f. Fragment: unp residues 9-364. Synonym: sk 1, spk 1. Engineered: yes
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Source:
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Homo sapiens. Organism_taxid: 9606. Cell_line: sf9. Gene: sphk1, sphk, spk.
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Resolution:
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2.30Å
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R-factor:
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0.232
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R-free:
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0.285
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Authors:
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X.Min,N.P.Walker,Z.Wang
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Key ref:
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Z.Wang
et al.
(2013).
Molecular basis of sphingosine kinase 1 substrate recognition and catalysis.
Structure,
21,
798-809.
PubMed id:
DOI:
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Date:
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11-Oct-12
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Release date:
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08-May-13
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PROCHECK
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Headers
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References
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Q9NYA1
(SPHK1_HUMAN) -
Sphingosine kinase 1 from Homo sapiens
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Seq:
Struc:
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384 a.a.
347 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Enzyme class 1:
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E.C.2.3.1.-
- ?????
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Enzyme class 2:
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E.C.2.7.1.91
- sphingosine kinase.
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Reaction:
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a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H+
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sphingoid base
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+
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ATP
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=
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sphingoid 1-phosphate
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+
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ADP
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Structure
21:798-809
(2013)
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PubMed id:
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Molecular basis of sphingosine kinase 1 substrate recognition and catalysis.
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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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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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