View source for 8st4


==The 2alpha3beta stoichiometry of human alpha4beta2 nicotinic acetylcholine receptor in complex with acetylcholine==
<StructureSection load='8st4' size='340' side='right'caption='[[8st4]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8st4]] 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=8ST4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ST4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.35&#8491;</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=8st4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8st4 OCA], [https://pdbe.org/8st4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8st4 RCSB], [https://www.ebi.ac.uk/pdbsum/8st4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8st4 ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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> 
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== Publication Abstract from PubMed ==
BACKGROUND AND PURPOSE: alpha4beta2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin potentiation are not known. EXPERIMENTAL APPROACH: To identify calcium binding sites, we applied cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulations to each stoichiometric form of the alpha4beta2 nACh receptor in the presence of calcium ions. To test whether the identified calcium sites are linked to potentiation, we generated mutants of anionic residues at the sites, expressed wild type and mutant receptors in clonal mammalian fibroblasts, and recorded ACh-elicited single-channel currents with or without calcium. KEY RESULTS: Both cryo-EM and MD simulations show calcium bound to a site between the extracellular and transmembrane domains of each alpha4 subunit (ECD-TMD site). Substituting alanine for anionic residues at the ECD-TMD site abolishes stoichiometry-selective calcium potentiation, as monitored by single-channel patch clamp electrophysiology. Additionally, MD simulation reveals calcium association at subunit interfaces within the extracellular domain. Substituting alanine for anionic residues at the ECD sites reduces or abolishes stoichiometry-selective calcium potentiation. CONCLUSIONS AND IMPLICATIONS: Stoichiometry-selective calcium potentiation of the alpha4beta2 nACh receptor is achieved by calcium association with topographically distinct sites framed by anionic residues within the alpha4 subunit and between the alpha4 and beta2 subunits. Stoichiometry-selective calcium potentiation could result from the greater number of calcium sites in the stoichiometric form with three rather than two alpha4 subunits. The results are relevant to modulation of signalling via alpha4beta2 nACh receptors in physiological and pathophysiological conditions.

Structural bases for stoichiometry-selective calcium potentiation of a neuronal nicotinic receptor.,Mazzaferro S, Kang G, Natarajan K, Hibbs RE, Sine SM Br J Pharmacol. 2024 Jul;181(13):1973-1992. doi: 10.1111/bph.16321. Epub 2024 Mar , 7. PMID:38454578<ref>PMID:38454578</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
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== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Hibbs RE]]
[[Category: Kang G]]