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==Cryo-EM structure of Torpedo acetylcholine receptor in complex with alpha-bungarotoxin== | ==Cryo-EM structure of Torpedo acetylcholine receptor in complex with alpha-bungarotoxin== | ||
<StructureSection load='6uwz' size='340' side='right'caption='[[6uwz]]' scene=''> | <StructureSection load='6uwz' size='340' side='right'caption='[[6uwz]], [[Resolution|resolution]] 2.69Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UWZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UWZ FirstGlance]. <br> | <table><tr><td colspan='2'>[[6uwz]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UWZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UWZ FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwz OCA], [http://pdbe.org/6uwz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwz RCSB], [http://www.ebi.ac.uk/pdbsum/6uwz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwz ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OCT:N-OCTANE'>OCT</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=P1L:S-PALMITOYL-L-CYSTEINE'>P1L</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uwz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwz OCA], [http://pdbe.org/6uwz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwz RCSB], [http://www.ebi.ac.uk/pdbsum/6uwz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwz ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACHG_TETCF ACHG_TETCF]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [[http://www.uniprot.org/uniprot/ACHA_TETCF ACHA_TETCF]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [[http://www.uniprot.org/uniprot/ACHB_TETCF ACHB_TETCF]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [[http://www.uniprot.org/uniprot/ACHD_TETCF ACHD_TETCF]] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [[http://www.uniprot.org/uniprot/3L21A_BUNMU 3L21A_BUNMU]] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).<ref>PMID:16549768</ref> <ref>PMID:25634239</ref> <ref>PMID:9305882</ref> <ref>PMID:9840221</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of alpha-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located approximately 60 A from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes. | |||
Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.,Rahman MM, Teng J, Worrell BT, Noviello CM, Lee M, Karlin A, Stowell MHB, Hibbs RE Neuron. 2020 Apr 2. pii: S0896-6273(20)30219-1. doi:, 10.1016/j.neuron.2020.03.012. PMID:32275860<ref>PMID:32275860</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6uwz" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hibbs | [[Category: Tetronarce californica]] | ||
[[Category: Karlin A]] | [[Category: Hibbs, R E]] | ||
[[Category: Lee M]] | [[Category: Karlin, A]] | ||
[[Category: Noveillo | [[Category: Lee, M]] | ||
[[Category: Rahman | [[Category: Noveillo, C M]] | ||
[[Category: Stowell M]] | [[Category: Rahman, M M]] | ||
[[Category: Teng J]] | [[Category: Stowell, M]] | ||
[[Category: Worrell | [[Category: Teng, J]] | ||
[[Category: Worrell, B T]] | |||
[[Category: Cys-loop receptor]] | |||
[[Category: Ion channel]] | |||
[[Category: Neurotoxin]] | |||
[[Category: Nicotinic acetylcholine receptor]] | |||
[[Category: Nicotinic receptor]] | |||
[[Category: Torpedo]] | |||
[[Category: Transport protein]] | |||
Latest revision as of 09:10, 22 April 2020
Cryo-EM structure of Torpedo acetylcholine receptor in complex with alpha-bungarotoxinCryo-EM structure of Torpedo acetylcholine receptor in complex with alpha-bungarotoxin
Structural highlights
Function[ACHG_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHA_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHB_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [ACHD_TETCF] After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. [3L21A_BUNMU] Binds with high affinity to muscular (tested on Torpedo marmorata, Kd=0.4 nM) and neuronal (tested on chimeric alpha-7/CHRNA7, Kd=0.95 nM) nicotinic acetylcholine receptor (nAChR) and inhibits acetylcholine from binding to the receptor, thereby impairing neuromuscular and neuronal transmission (PubMed:9305882). It also shows an activity on GABA(A) receptors (PubMed:16549768, PubMed:25634239). It antagonises GABA-activated currents with high potency when tested on primary hippocampal neurons (PubMed:25634239). It inhibits recombinantly expressed GABA(A) receptors composed of alpha-2-beta-2-gamma-2 (GABRA2-GABRB2-GABRG2) subunits with high potency (62.3% inhibition at 20 uM of toxin) (PubMed:25634239). It also shows a weaker inhibition on GABA(A) receptors composed of alpha-1-beta-2-gamma-2 (GABRA1-GABRB2-GABRG2) subunits, alpha-4-beta-2-gamma-2 (GABRA4-GABRB2-GABRG2) subunits, and alpha-5-beta-2-gamma-2 (GABRA5-GABRB2-GABRG2) subunits (PubMed:25634239). A very weak inhibition is also observed on GABA(A) receptor composed of alpha-1-beta-3-gamma-2 (GABRA1-GABRB3-GABRG2) (PubMed:26221036). It has also been shown to bind and inhibit recombinant GABA(A) receptor beta-3/GABRB3 subunit (Kd=about 50 nM) (PubMed:16549768). In addition, it blocks the extracellular increase of dopamine evoked by nicotine only at the higher dose (4.2 uM) (PubMed:9840221).[1] [2] [3] [4] Publication Abstract from PubMedThe nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of alpha-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located approximately 60 A from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes. Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.,Rahman MM, Teng J, Worrell BT, Noviello CM, Lee M, Karlin A, Stowell MHB, Hibbs RE Neuron. 2020 Apr 2. pii: S0896-6273(20)30219-1. doi:, 10.1016/j.neuron.2020.03.012. PMID:32275860[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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