Binding site of AChR: Difference between revisions

<StructureSection load='1hc9' size='450' side='right' background='none' caption='structure of binding site of AChR' scene='68/688431/Complex_of_btx_and_hap/1' >

Acetylcholine receptor is a member of pentameric ligand gated ion channels family,which share the similar structure. Pentameric ligand gated ion channels (pLGIC), or [http://en.wikipedia.org/wiki/Cys-loop_receptors Cys-loop receptors],are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a chemical messenger, such as a neurotransmitter<ref> Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 156–7. ISBN 978-0-87893-697-7.</ref>. In overall organization, the <scene name='68/688431/Plgics/1'>pLGICs</scene> 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.<ref>PMID:24167270</ref> 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 (M1, M2, M3, M4).  

The mechanism of pLGIC is provided by Prof. Jean-Pierre Changeux in the paper 'X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation'(Nature,2009): helices M1, M2 and M3, and a large portion of the β-sandwich consisting of strands β1, β2, β6, β7 and β10, these elements constitute the subunit ‘common core’. Common core superimposition shows that the GLIC subunits display a quaternary twist compared to ELIC, with anticlockwise (versus clockwise) rotation in the upper (versus lower) part of the pentamer, when viewed from the extracellular compartment (Fig. 3a). This is confirmed by normal mode analysis: the lowest frequency mode is precisely a twist mode and has by far the highest contribution (29%) to the transition. However, we note that the first 100 lowest-frequency modes (usually the most collective ones) only explain about 50% of the transition. Other and more local movements occur:in the TMD, the outer ends of M2 and M3 of GLIC are tilted away radially from the channel axis, while the outer end of M1 is fixed. The inner ends of M1, M2 and M3 move tangentially towards the left, when viewed from the membrane (Fig. 3b). In the ECD, the core of the b-sandwich undergoes little deformation, but is rotated by 8u around an axis roughly perpendicular to the inner sheet of the β-sandwich (Fig. 3a), concomitant with a rearrangement of both the subunit–subunit and the ECD/TMD interfaces, regions known to contribute to neurotransmitter gating. The latter contains the well-conserved β6–β7 and M2–M3 loops and the b1–b2 loop whose length is conserved in the pLGIC family. We observe a downward motion of the β1–β2 loop, concomitant with a displacement of the M2–M3 loop, M2 and M3 helices and b6–b7 loop towards the periphery of the molecule (Fig. 3c), thereby opening the pore. Such twist to open motions, initially proposed from ab initio normal mode analysis of nAChRs, and observed for Kcsa, may plausibly be extended to eukaryotic pLGICs. The structural transition described here couples in an allosteric manner the opening–closing motion of the pore with distant binding sites—located at the ECD subunit interface for neurotransmitters, or within the TMD for allosteric effectors30—and may possibly serve as a general mechanism of signal transduction in pLGICs<ref name="Bocquet2009" />.

Nicotinic AChRs is neuron receptor protein that singal for muscular contraction upon the chemical stimulus.It may exist in different interconvertible conformational states. Binding of an agonist stabilises the open and desensitised states. Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively-charged ions is inward.<ref>http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor</ref>

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. Some 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.<ref>PMID:18327915</ref>