Introduction
There are two kinds of acetylcholine receptor in nature: nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. The nicotinic acetylcholine receptor(nAChR) is a ligand gated ion channel activated by binding of acetylcholine in nature. In this page we will show the binding site of nAChR.
Pentameric ligand-gated ion channel
Pentameric ligand gated ion channels(), or Cys-loop receptors,mediate rapid chemical transmission of signals. Nicotinic acetylcholine receptor is a kind of pentameric ligand gated ion channels. So at first of this page, we introduce some facts of the pentameric ligand gated ion channels, which will help us to understand the structure and function of AChR.
In overall organization, the pLGIC have five subunits. The five subunits are arranged in a barrel-like manner around a central symmetry axis that coincides with the ion permeation pathway.[1] In each subunit, the extracellular domin(ECD) of pLGIC encompasses 10β-strands that are organized as a sandwich of two tightly interacting β-sheets, while the transmembrane domain(TMD) folds into a bundle of four α-helices.
Structure of Acetylcholine binding site
Function of Acetylcholine receptor
The α-Neurotoxins such as α-bungarotoxin (α-BTX)can compete antagonists of acetylcholine for its site. So study the binding site of AChR is very important for the development of antidotesagainstα-BTX poisoning as well as drugs against, like Alzheimer's disease and nicotine addiction.
The X-ray structure of AChR has not yet been solved since its hydrophobic character hampers its successful crystallization. So in this page,[2] We will use a complex of α-bungarotoxinwith a high affinity 13-residue peptide that is homologous to the αsubunit of AChR to study the AChR binding site in general. We also will present the Acetylcholine binding protein and the general pentameric ligand gated ion channels to help you understand this kind of structure and their function.
The nAChR is unable to bind ACh when bound to any of the snake venom α-neurotoxins. These α-neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis and death. The nAChR contains two binding sites for snake venom neurotoxins. Progress towards discovering the dynamics of binding action of these sites has proved difficult, although recent studies using normal mode dynamics[13] have aided in predicting the nature of both the binding mechanisms of snake toxins and of ACh to nAChRs. These studies have shown that a twist-like motion caused by ACh binding is likely responsible for pore opening, and that one or two molecules of α-bungarotoxin (or other long-chain α-neurotoxin) suffice to halt this motion. The toxins seem to lock together neighboring receptor subunits, inhibiting the twist and therefore, the opening motion.[3]
Superimpose HAP on AChBP
The superimposed model of AChBP and α-BTX suggests that the putative agonist HEPES seen in the AChBP structure is blocked from entering or leaving the AChBP interface cleft by the insertion of loop 2 of α-BTX into that cleft.
The major interactions between α-BTX and the HAP, and by the analogy to the AChR α-subunit, occur in residues 187–192 of that subunit.
The superposition of the HAP on loop 182–193 of AChBP reveals the α-BTX to fit exquisitely into the interface of two subunits of the pentameric AChBP.
Loop 2 of the toxin is inserted into the interface of two adjacent subunits of AChBP with relatively minor clashes between AChBP and α-BTX.
The possible formation of an intermolecular salt bridge between AChR and α-BTX at that positionmay provide further explanation to the high affinity of binding of the toxin to the receptor.This notion is supported by recent studies on charge reversal mutations of basic residues on loop 2 of α-neurotoxin
So the possible formation of an intermolecular salt bridge between AChR and α-BTX at that position may provide further explanation to the high affinity of binding of the toxin to the receptor.
