Binding site of AChR
From Proteopedia
| Line 8: | Line 8: | ||
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.<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. | 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.<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. | ||
| - | == Function of Acetylcholine receptor == | ||
| - | The α-Neurotoxins such as [http://en.wikipedia.org/wiki/Alpha-Bungarotoxin 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 [http://en.wikipedia.org/wiki/Alzheimer's_disease Alzheimer's disease] and [http://en.wikipedia.org/wiki/Nicotine 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,<ref>PMID:11683996</ref> 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 [http://proteopedia.org/wiki/index.php/Acetylcholine_binding_protein Acetylcholine binding protein] and the general [http://proteopedia.org/wiki/index.php/4hfi 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.<ref>PMID:18327915</ref> | ||
| - | |||
| - | <scene name='68/688431/An_open-pore_structure/1'>An Open-Pore Structure Of A Bacterial Pentameric Ligand- Gated Ion Channel</scene> | ||
| - | == Structure of Acetylcholine binding site == | ||
== Superimpose HAP on AChBP == | == Superimpose HAP on AChBP == | ||
| Line 32: | Line 23: | ||
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. | 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. | ||
</StructureSection> | </StructureSection> | ||
| + | == Function of Acetylcholine receptor == | ||
| + | The α-Neurotoxins such as [http://en.wikipedia.org/wiki/Alpha-Bungarotoxin 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 [http://en.wikipedia.org/wiki/Alzheimer's_disease Alzheimer's disease] and [http://en.wikipedia.org/wiki/Nicotine 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,<ref>PMID:11683996</ref> 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 [http://proteopedia.org/wiki/index.php/Acetylcholine_binding_protein Acetylcholine binding protein] and the general [http://proteopedia.org/wiki/index.php/4hfi 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.<ref>PMID:18327915</ref> | ||
| + | |||
| + | <scene name='68/688431/An_open-pore_structure/1'>An Open-Pore Structure Of A Bacterial Pentameric Ligand- Gated Ion Channel</scene> | ||
| + | == Structure of Acetylcholine binding site == | ||
| + | |||
| + | |||
Revision as of 19:32, 22 January 2015
| |||||||||||
Contents |
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]
Structure of Acetylcholine binding site
Quiz
References
- ↑ Gonzalez-Gutierrez G, Cuello LG, Nair SK, Grosman C. Gating of the proton-gated ion channel from Gloeobacter violaceus at pH 4 as revealed by X-ray crystallography. Proc Natl Acad Sci U S A. 2013 Oct 28. PMID:24167270 doi:http://dx.doi.org/10.1073/pnas.1313156110
- ↑ Harel M, Kasher R, Nicolas A, Guss JM, Balass M, Fridkin M, Smit AB, Brejc K, Sixma TK, Katchalski-Katzir E, Sussman JL, Fuchs S. The binding site of acetylcholine receptor as visualized in the X-Ray structure of a complex between alpha-bungarotoxin and a mimotope peptide. Neuron. 2001 Oct 25;32(2):265-75. PMID:11683996
- ↑ Samson AO, Levitt M. Inhibition mechanism of the acetylcholine receptor by alpha-neurotoxins as revealed by normal-mode dynamics. Biochemistry. 2008 Apr 1;47(13):4065-70. doi: 10.1021/bi702272j. Epub 2008 Mar 8. PMID:18327915 doi:http://dx.doi.org/10.1021/bi702272j
Proteopedia Page Contributors and Editors (what is this?)
Ma Zhuang, Zicheng Ye, Angel Herraez, Alexander Berchansky, Michal Harel
