PDBsum entry 5m0s

Hydrolase

PDB id: 5m0s

Contents

Protein chain

777 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN-MAN-MAN-MAN-MAN

7CW

SCN ×11

GOL ×5

Metals

IOD ×13

_CA

_ZN ×2

_NA

Waters ×89

PDB id:

5m0s

Name:

Hydrolase

Title:

Structure-based evolution of a hybrid steroid series of autotaxin inhibitors

Structure:

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

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: enpp2, atx, npps2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293. Expression_system_organ: kidney

Resolution:

2.10Å R-factor: 0.240 R-free: 0.286

Authors:

W.-J.Keune,T.Heidebrecht,A.Perrakis

Key ref:

W.J.Keune et al. (2017). Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators. J Med Chem, 60, 2006-2017. PubMed id: 28165241 DOI: 10.1021/acs.jmedchem.6b01743

Date:

05-Oct-16 Release date: 16-Aug-17

Protein chain

Q64610  (ENPP2_RAT) -  Autotaxin from Rattus norvegicus

Seq: 887 a.a.

Struc: 777 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1021/acs.jmedchem.6b01743

J Med Chem 60:2006-2017 (2017)

PubMed id: 28165241

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.

W.J.Keune, F.Potjewyd, T.Heidebrecht, F.Salgado-Polo, S.J.Macdonald, L.Chelvarajan, A.Abdel Latif, S.Soman, A.J.Morris, A.J.Watson, C.Jamieson, A.Perrakis.

ABSTRACT

Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.