PDBsum entry 4y2s

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4y2s

Contents

Protein chain

546 a.a.

Ligands

49P

Metals

_MG

Waters ×71

PDB id:

4y2s

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Structure of soluble epoxide hydrolase in complex with 1-[3- (trifluoromethyl)phenyl]-1h-pyrazol-4-ol

Structure:

Bifunctional epoxide hydrolase 2. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ephx2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.197 R-free: 0.233

Authors:

Y.Amano,T.Yamaguchi

Key ref:

Y.Amano et al. (2015). Identification of N-ethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening. Bioorg Med Chem Lett, 23, 2310-2317. PubMed id: 25862210 DOI: 10.1016/j.bmc.2015.03.083

Date:

10-Feb-15 Release date: 06-May-15

Protein chain

P34913  (HYES_HUMAN) -  Bifunctional epoxide hydrolase 2 from Homo sapiens

Seq: 555 a.a.

Struc: 546 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.1.3.76 - lipid-phosphate phosphatase.
• Reaction: (9S,10S)-10-hydroxy-9-(phosphooxy)octadecanoate + H2O = (9S,10S)-9,10- dihydroxyoctadecanoate + phosphate
• Cofactor: Mg(2+)
• Enzyme class 3: E.C.3.3.2.10 - soluble epoxide hydrolase.
• Reaction: an epoxide + H2O = an ethanediol

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: 10.1016/j.bmc.2015.03.083

Bioorg Med Chem Lett 23:2310-2317 (2015)

PubMed id: 25862210

Identification of N-ethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening.

Y.Amano, E.Tanabe, T.Yamaguchi.

ABSTRACT

Soluble epoxide hydrolase (sEH) is a potential target for the treatment of inflammation and hypertension. X-ray crystallographic fragment screening was used to identify fragment hits and their binding modes. Eight fragment hits were identified via soaking of sEH crystals with fragment cocktails, and the co-crystal structures of these hits were determined via individual soaking. Based on the binding mode, N-ethylmethylamine was identified as a promising scaffold that forms hydrogen bonds with the catalytic residues of sEH, Asp335, Tyr383, and Tyr466. Compounds containing this scaffold were selected from an in-house chemical library and assayed. Although the starting fragment had a weak inhibitory activity (IC50: 800μM), we identified potent inhibitors including 2-({[2-(adamantan-1-yl)ethyl]amino}methyl)phenol exhibiting the highest inhibitory activity (IC50: 0.51μM). This corresponded to a more than 1500-fold increase in inhibitory activity compared to the starting fragment. Co-crystal structures of the hit compounds demonstrate that the binding of N-ethylmethylamine to catalytic residues is similar to that of the starting fragment. We therefore consider crystallographic fragment screening to be appropriate for the identification of weak but promising fragment hits.