Colletier_2006_EMBO.J_25_2746

Reference

Title : Structural insights into substrate traffic and inhibition in acetylcholinesterase - Colletier_2006_EMBO.J_25_2746
Author(s) : Colletier JP , Fournier D , Greenblatt HM , Stojan J , Sussman JL , Zaccai G , Silman I , Weik M
Ref : EMBO Journal , 25 :2746 , 2006
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.

PubMedSearch : Colletier_2006_EMBO.J_25_2746
PubMedID: 16763558
Gene_locus related to this paper: torca-ACHE

Citations formats

Colletier JP, Fournier D, Greenblatt HM, Stojan J, Sussman JL, Zaccai G, Silman I, Weik M (2006)
Structural insights into substrate traffic and inhibition in acetylcholinesterase
EMBO Journal 25 :2746

Colletier JP, Fournier D, Greenblatt HM, Stojan J, Sussman JL, Zaccai G, Silman I, Weik M (2006)
EMBO Journal 25 :2746