PDBsum entry 5nap

Hydrolase

PDB id: 5nap

Contents

Protein chain

532 a.a.

Ligands

NAG-FUC

NAG-NAG-BMA-MAN ×2

DZ7

Waters ×425

PDB id:

5nap

Name:

Hydrolase

Title:

Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like inhibitor 17

Structure:

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

Source:

Tetronarce californica. Pacific electric ray. Organism_taxid: 7787

Resolution:

2.17Å R-factor: 0.172 R-free: 0.210

Authors:

R.Caliandro,A.Pesaresi,D.Lamba

Key ref:

R.Caliandro et al. (2018). Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues. J Enzyme Inhib Med Chem, 33, 794-803. PubMed id: 29651884 DOI: 10.1080/14756366.2018.1458030

Date:

28-Feb-17 Release date: 02-May-18

Protein chain

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: 10.1080/14756366.2018.1458030

J Enzyme Inhib Med Chem 33:794-803 (2018)

PubMed id: 29651884

Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues.

R.Caliandro, A.Pesaresi, L.Cariati, A.Procopio, M.Oliverio, D.Lamba.

ABSTRACT

Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with K_i values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity.