PDBsum entry 6ezh

Hydrolase

PDB id: 6ezh

Contents

Protein chains

532 a.a.

Ligands

NAG ×4

C6H ×2

Waters ×550

PDB id:

6ezh

Name:

Hydrolase

Title:

Torpedo californica ache in complex with indolic multi-target directed ligand

Structure:

Acetylcholinesterase. Chain: a, b. Synonym: ache. Ec: 3.1.1.7

Source:

Tetronarce californica. Pacific electric ray. Organism_taxid: 7787

Resolution:

2.60Å R-factor: 0.223 R-free: 0.273

Authors:

G.Santoni,J.Lalut,D.Karila,C.Lecoutey,A.Davis,F.Nachon,I.Sillman, J.Sussman,M.Weik,T.Maurice,P.Dallemagne,C.Rochais

Key ref:

J.Lalut et al. (2018). Novel multitarget-directed ligands targeting acetylcholinesterase and σ₁ receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase. Eur J Med Chem, 162, 234-248. PubMed id: 30447434 DOI: 10.1016/j.ejmech.2018.10.064

Date:

15-Nov-17 Release date: 21-Nov-18

Protein chains

P04058  (ACES_TETCF) -  Acetylcholinesterase from Tetronarce californica

Seq: 586 a.a.

Struc: 532 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.1.7 - acetylcholinesterase.
• Reaction: acetylcholine + H2O = choline + acetate + H⁺

acetylcholine (Bound ligand (Het Group name = NAG) matches with 41.18% similarity) + H2O = choline + acetate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2018.10.064

Eur J Med Chem 162:234-248 (2018)

PubMed id: 30447434

Novel multitarget-directed ligands targeting acetylcholinesterase and σ₁ receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase.

J.Lalut, G.Santoni, D.Karila, C.Lecoutey, A.Davis, F.Nachon, I.Silman, J.Sussman, M.Weik, T.Maurice, P.Dallemagne, C.Rochais.

ABSTRACT

Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT₄ receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ₁ receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.