PDBsum entry 3wav

Hydrolase/hydrolase inhibitor

PDB id: 3wav

Contents

Protein chain

801 a.a.

Ligands

NAG-NAG ×2

NAG-NAG-BMA-MAN-MAN-MAN

SCN ×2

EDO ×18

SO4

DWV

Metals

_ZN ×2

_CA

_NA

__K

Waters ×423

PDB id:

3wav

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of autotaxin in complex with compound 10

Structure:

Ectonucleotide pyrophosphatase/phosphodiesterase family member 2. Chain: a. Synonym: atx, e-npp 2, autotaxin, extracellular lysophospholipase d, lysopld. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: enpp2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s gnt1-.

Resolution:

1.80Å R-factor: 0.189 R-free: 0.223

Authors:

H.Nishimasu,R.Ishitani,O.Nureki

Key ref:

M.Kawaguchi et al. (2013). Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe. Acs Chem Biol, 8, 1713-1721. PubMed id: 23688339 DOI: 10.1021/cb400150c

Date:

09-May-13 Release date: 31-Jul-13

Protein chain

Q9R1E6  (ENPP2_MOUSE) -  Autotaxin from Mus musculus

Seq: 862 a.a.

Struc: 801 a.a.

Enzyme reactions

• Enzyme class 1: E.C.3.1.4.39 - alkylglycerophosphoethanolamine phosphodiesterase.
• Reaction: a 1-O-alkyl-sn-glycero-3-phosphoethanolamine + H2O = a 1-O-alkyl- sn-glycero-3-phosphate + ethanolamine + H⁺

1-O-alkyl-sn-glycero-3-phosphoethanolamine + H2O = 1-O-alkyl- sn-glycero-3-phosphate + ethanolamine (Bound ligand (Het Group name = EDO) matches with 60.00% similarity) + H(+)

• Enzyme class 2: E.C.3.1.4.4 - phospholipase D.
• Reaction: a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1,2-diacyl-sn-glycero- 3-phosphate + choline + 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

reference

DOI no: 10.1021/cb400150c

Acs Chem Biol 8:1713-1721 (2013)

PubMed id: 23688339

Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe.

M.Kawaguchi, T.Okabe, S.Okudaira, H.Nishimasu, R.Ishitani, H.Kojima, O.Nureki, J.Aoki, T.Nagano.

ABSTRACT

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), was originally identified as a tumor cell autocrine motility factor and was found to be identical to plasma lysophospholipase D, which is the predominant contributor to lysophosphatidic acid (LPA) production from lysophospholipids. ATX is therefore considered to regulate the physiological and pathological roles of LPA, including angiogenesis, lymphocyte trafficking, tissue fibrosis, and cancer cell invasion and metastasis. Thus, it is a potential therapeutic target. Here, we first developed a sensitive and specific ATX fluorescence probe, TG-mTMP, and used it to screen ATX inhibitors in a large chemical library. This probe, which is superior to previously available probes FS-3 and CPF4 in terms of sensitivity or specificity, enabled us to identify several novel ATX inhibitor scaffolds. We solved the crystal structures of ATX complexes with the hit compounds at high resolution (1.75-1.95 Å) and used this information to guide optimization of the structure of a selected inhibitor. The optimized compounds, 3BoA and its derivatives, exhibited potent ATX-inhibitory activity both in vitro and in vivo. These inhibitors are expected to be useful tools to understand the roles of ATX in vitro and in vivo and may also be candidate anti-ATX therapeutic agents.