PDBsum entry 6leh

Hydrolase

PDB id: 6leh

Contents

Protein chain

783 a.a.

Ligands

NAG-NAG-MAN-MAN-MAN-MAN

NAG-NAG-MAN

SO4

EDO ×17

EAR

Metals

_ZN ×2

_CA

_NA

__K

_CL ×2

Waters ×233

PDB id:

6leh

Name:

Hydrolase

Title:

Crystal structure of autotaxin in complex with an inhibitor

Structure:

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

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: enpp2, npps2, pdnp2. Expressed in: homo sapiens. Expression_system_taxid: 9606

Resolution:

2.00Å R-factor: 0.192 R-free: 0.237

Authors:

H.Nishimasu,N.Osamu

Key ref:

M.Kawaguchi et al. (2020). Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain. J Med Chem, 63, 3188-3204. PubMed id: 32134652 DOI: 10.1021/acs.jmedchem.9b01967

Date:

25-Nov-19 Release date: 18-Mar-20

Protein chain

Q9R1E6  (ENPP2_MOUSE) -  Autotaxin from Mus musculus

Seq: 862 a.a.

Struc: 783 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/acs.jmedchem.9b01967

J Med Chem 63:3188-3204 (2020)

PubMed id: 32134652

Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain.

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

ABSTRACT

Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.