PDBsum entry 4zg6

Hydrolase/hydrolase inhibitor

PDB id: 4zg6

Contents

Protein chains

754 a.a.

Ligands

NAG-NAG-BMA ×2

GOL ×2

4NY ×2

SCN ×12

Metals

_ZN ×4

_CA ×2

_NA ×4

Waters ×614

PDB id:

4zg6

Name:

Hydrolase/hydrolase inhibitor

Title:

Structural basis for inhibition of human autotaxin by four novel compounds

Structure:

Ectonucleotide pyrophosphatase/phosphodiesterase family member 2. Chain: a, b. Fragment: unp residues 17-863. Synonym: e-npp 2,autotaxin,extracellular lysophospholipase d,lysopld. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: enpp2, atx, pdnp2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.80Å R-factor: 0.223 R-free: 0.265

Authors:

A.J.Stein,G.Bain,J.H.Hutchinson,J.F.Evans

Key ref:

A.J.Stein et al. (2015). Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding. Mol Pharmacol, 88, 982-992. PubMed id: 26371182 DOI: 10.1124/mol.115.100404

Date:

22-Apr-15 Release date: 14-Oct-15

Protein chains

Q13822  (ENPP2_HUMAN) -  Autotaxin from Homo sapiens

Seq: 863 a.a.

Struc: 754 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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 = GOL) matches with 42.86% 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: 10.1124/mol.115.100404

Mol Pharmacol 88:982-992 (2015)

PubMed id: 26371182

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.

A.J.Stein, G.Bain, P.Prodanovich, A.M.Santini, J.Darlington, N.M.Stelzer, R.S.Sidhu, J.Schaub, L.Goulet, D.Lonergan, I.Calderon, J.F.Evans, J.H.Hutchinson.

ABSTRACT

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.