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| | ==Structure of the 2alpha3beta stiochiometry of the human Alpha4Beta2 nicotinic receptor== | | ==Structure of the 2alpha3beta stiochiometry of the human Alpha4Beta2 nicotinic receptor== |
| - | <SX load='6cnj' size='340' side='right' viewer='molstar' caption='[[6cnj]], [[Resolution|resolution]] 3.40Å' scene=''> | + | <SX load='6cnj' size='340' side='right' viewer='molstar' caption='[[6cnj]], [[Resolution|resolution]] 3.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cnj]] is a 11 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNJ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CNJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cnj]] is a 11 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CNJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CNJ FirstGlance]. <br> |
| - | </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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NCT:(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE'>NCT</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHRNA4, NACRA4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CHRNB2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NCT:(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE'>NCT</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=6cnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnj OCA], [http://pdbe.org/6cnj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cnj RCSB], [http://www.ebi.ac.uk/pdbsum/6cnj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnj ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6cnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cnj OCA], [https://pdbe.org/6cnj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cnj RCSB], [https://www.ebi.ac.uk/pdbsum/6cnj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cnj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN]] Autosomal dominant nocturnal frontal lobe epilepsy. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/ACHB2_HUMAN ACHB2_HUMAN]] Defects in CHRNB2 are the cause of nocturnal frontal lobe epilepsy type 3 (ENFL3) [MIM:[http://omim.org/entry/605375 605375]]. ENFL3 is an autosomal dominant epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements.<ref>PMID:11062464</ref> <ref>PMID:11104662</ref> | + | [https://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN] Autosomal dominant nocturnal frontal lobe epilepsy. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN]] 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 permeable to sodium ions.<ref>PMID:22361591</ref> [[http://www.uniprot.org/uniprot/ACHB2_HUMAN ACHB2_HUMAN]] 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 permeable to sodiun ions.<ref>PMID:22361591</ref> | + | [https://www.uniprot.org/uniprot/ACHA4_HUMAN ACHA4_HUMAN] 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 permeable to sodium ions.<ref>PMID:22361591</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Gharpure, A]] | + | [[Category: Gharpure A]] |
| - | [[Category: Hibbs, R E]] | + | [[Category: Hibbs RE]] |
| - | [[Category: Jr, R M.Walsh]]
| + | [[Category: Morales-Perez CL]] |
| - | [[Category: Morales-Perez, C L]] | + | [[Category: Roh SH]] |
| - | [[Category: Roh, S H]] | + | [[Category: Teng J]] |
| - | [[Category: Teng, J]] | + | [[Category: Walsh Jr RM]] |
| - | [[Category: Acetylcholine receptor]] | + | |
| - | [[Category: Cys-loop receptor]]
| + | |
| - | [[Category: Ligand-gated ion channel]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Disease
ACHA4_HUMAN Autosomal dominant nocturnal frontal lobe epilepsy. The disease is caused by mutations affecting the gene represented in this entry.
Function
ACHA4_HUMAN 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 permeable to sodium ions.[1]
Publication Abstract from PubMed
Fast chemical communication in the nervous system is mediated by neurotransmitter-gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries (1) . This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The alpha4beta2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of alpha- and beta-subunits (2alpha:3beta and 3alpha:2beta). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction(2,3) and congenital epilepsy(4,5). Here we leverage cryo-electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to beta2 were used to 'break' symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results reveal principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacological properties of the two different stoichiometries of this receptor.
Structural principles of distinct assemblies of the human alpha4beta2 nicotinic receptor.,Walsh RM Jr, Roh SH, Gharpure A, Morales-Perez CL, Teng J, Hibbs RE Nature. 2018 May 2. pii: 10.1038/s41586-018-0081-7. doi:, 10.1038/s41586-018-0081-7. PMID:29720657[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bondarenko V, Mowrey D, Tillman T, Cui T, Liu LT, Xu Y, Tang P. NMR structures of the transmembrane domains of the alpha4beta2 nAChR. Biochim Biophys Acta. 2012 Feb 14;1818(5):1261-1268. PMID:22361591 doi:10.1016/j.bbamem.2012.02.008
- ↑ Walsh RM Jr, Roh SH, Gharpure A, Morales-Perez CL, Teng J, Hibbs RE. Structural principles of distinct assemblies of the human alpha4beta2 nicotinic receptor. Nature. 2018 May 2. pii: 10.1038/s41586-018-0081-7. doi:, 10.1038/s41586-018-0081-7. PMID:29720657 doi:http://dx.doi.org/10.1038/s41586-018-0081-7
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