PDBsum entry 2c4h

Hydrolase

PDB id: 2c4h

Contents

Protein chain

533 a.a. *

Ligands

NAG ×2

PGE ×2

AT3 ×2

ACE

ACT

Metals

_CL ×11

Waters ×948

* Residue conservation analysis

PDB id:

2c4h

Name:

Hydrolase

Title:

Torpedo californica acetylcholinesterase in complex with 500mm acetylthiocholine

Structure:

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

Source:

Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque

Resolution:

2.15Å R-factor: 0.169 R-free: 0.209

Authors:

J.P.Colletier,D.Fournier,H.M.Greenblatt,J.L.Sussman,G.Zaccai, I.Silman,M.Weik

Key ref:

J.P.Colletier et al. (2006). Structural insights into substrate traffic and inhibition in acetylcholinesterase. EMBO J, 25, 2746-2756. PubMed id: 16763558 DOI: 10.1038/sj.emboj.7601175

Date:

19-Oct-05 Release date: 14-Jun-06

Protein chain

P04058  (ACES_TETCF) -  Acetylcholinesterase from Tetronarce californica

Seq: 586 a.a.

Struc: 533 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 (Bound ligand (Het Group name = ACT) corresponds exactly) + acetate (Bound ligand (Het Group name = AT3) matches with 54.55% similarity) + H(+)

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

reference

DOI no: 10.1038/sj.emboj.7601175

EMBO J 25:2746-2756 (2006)

PubMed id: 16763558

Structural insights into substrate traffic and inhibition in acetylcholinesterase.

J.P.Colletier, D.Fournier, H.M.Greenblatt, J.Stojan, J.L.Sussman, G.Zaccai, I.Silman, M.Weik.

ABSTRACT

Acetylcholinesterase (AChE) terminates nerve-impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter, acetylcholine. Substrate traffic in AChE involves at least two binding sites, the catalytic and peripheral anionic sites, which have been suggested to be allosterically related and involved in substrate inhibition. Here, we present the crystal structures of Torpedo californica AChE complexed with the substrate acetylthiocholine, the product thiocholine and a nonhydrolysable substrate analogue. These structures provide a series of static snapshots of the substrate en route to the active site and identify, for the first time, binding of substrate and product at both the peripheral and active sites. Furthermore, they provide structural insight into substrate inhibition in AChE at two different substrate concentrations. Our structural data indicate that substrate inhibition at moderate substrate concentration is due to choline exit being hindered by a substrate molecule bound at the peripheral site. At the higher concentration, substrate inhibition arises from prevention of exit of acetate due to binding of two substrate molecules within the active-site gorge.

Selected figure(s)

Figure 1.
Figure 1 3D structure of native TcAChE (pdb access code 1EA5), highlighting the catalytic triad in red, Trp84 in the CAS, Trp279 at the PAS, and the bottleneck residue Phe330 in blue.

Figure 8.
Figure 8 Molecular surfaces of the active-site gorge in native TcAChE (A), and in the OTMA/TcAChE (B), 20 mM TCh/TcAChE (C), 20 mM ATCh/TcAChE (D) and 500 mM ATCh/TcAChE (E) complexes. OTMA, ATCh and TCh are shown as yellow sticks, as is the acetyl group on Ser200 in (D, E).

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2006, 25, 2746-2756) copyright 2006.

Figures were selected by the author.