PDBsum entry 4l02

Transferase/transferase inhibitor

PDB id: 4l02

Contents

Protein chains

360 a.a.

340 a.a.

Ligands

1V2 ×3

Waters ×58

PDB id:

4l02

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of sphk1 with inhibitor

Structure:

Sphingosine kinase 1. Chain: a, b, c. Fragment: unp residues 9-364. Synonym: sk 1, spk 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sphingosine kinase 1, sphk, sphk1, spk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.75Å R-factor: 0.210 R-free: 0.255

Authors:

X.Min,N.Walker,Z.Wang

Key ref:

D.J.Gustin et al. (2013). Structure guided design of a series of sphingosine kinase (SphK) inhibitors. Bioorg Med Chem Lett, 23, 4608-4616. PubMed id: 23845219 DOI: 10.1016/j.bmcl.2013.06.030

Date:

30-May-13 Release date: 24-Jul-13

Protein chain

Q9NYA1  (SPHK1_HUMAN) -  Sphingosine kinase 1 from Homo sapiens

Seq: 384 a.a.

Struc: 360 a.a.*

Protein chains

Q9NYA1  (SPHK1_HUMAN) -  Sphingosine kinase 1 from Homo sapiens

Seq: 384 a.a.

Struc: 340 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B, C: E.C.2.3.1.- - ?????
• Enzyme class 2: Chains A, B, C: E.C.2.7.1.91 - sphingosine kinase.
• Reaction: a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H⁺

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.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2013.06.030

Bioorg Med Chem Lett 23:4608-4616 (2013)

PubMed id: 23845219

Structure guided design of a series of sphingosine kinase (SphK) inhibitors.

D.J.Gustin, Y.Li, M.L.Brown, X.Min, M.J.Schmitt, M.Wanska, X.Wang, R.Connors, S.Johnstone, M.Cardozo, A.C.Cheng, S.Jeffries, B.Franks, S.Li, S.Shen, M.Wong, H.Wesche, G.Xu, T.J.Carlson, M.Plant, K.Morgenstern, K.Rex, J.Schmitt, A.Coxon, N.Walker, F.Kayser, Z.Wang.

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.