View source for 7qne


==Cryo-EM structure of human full-length synaptic alpha1beta3gamma2 GABA(A)R in complex with Ro15-4513 and megabody Mb38==
<StructureSection load='7qne' size='340' side='right'caption='[[7qne]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qne]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QNE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QNE 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]] 2.7&#8491;</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D10:DECANE'>D10</scene>, <scene name='pdbligand=EIE:ethyl+8-azido-5-methyl-6-oxidanylidene-4~{H}-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate'>EIE</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=PIO:[(2R)-2-OCTANOYLOXY-3-[OXIDANYL-[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIS(OXIDANYL)-4,5-DIPHOSPHONOOXY-CYCLOHEXYL]OXY-PHOSPHORYL]OXY-PROPYL]+OCTANOATE'>PIO</scene></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=7qne FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qne OCA], [https://pdbe.org/7qne PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qne RCSB], [https://www.ebi.ac.uk/pdbsum/7qne PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qne ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GBRA1_HUMAN GBRA1_HUMAN] Juvenile myoclonic epilepsy;Childhood absence epilepsy;Dravet syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry.  Disease susceptibility is associated with variations affecting the gene represented in this entry.  Disease susceptibility is associated with variations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/GBRA1_HUMAN GBRA1_HUMAN] Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Type A gamma-aminobutyric acid receptors (GABA(A)Rs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits(1,2) and can be modulated by essential medicines including general anaesthetics and benzodiazepines(3). Human GABA(A)R subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABA(A)Rs assembled from alpha4, beta3 and delta subunits, and their counterparts incorporating gamma2 instead of delta subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, alpha1-containing receptors(4-7). This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABA(A)R arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data(8,9), we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABA(A)Rs.

Differential assembly diversifies GABA(A) receptor structures and signalling.,Sente A, Desai R, Naydenova K, Malinauskas T, Jounaidi Y, Miehling J, Zhou X, Masiulis S, Hardwick SW, Chirgadze DY, Miller KW, Aricescu AR Nature. 2022 Apr;604(7904):190-194. doi: 10.1038/s41586-022-04517-3. Epub 2022 , Mar 30. PMID:35355020<ref>PMID:35355020</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qne" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Aricescu AR]]
[[Category: Chirgadze DY]]
[[Category: Desai R]]
[[Category: Hardwick SW]]
[[Category: Jounaidi Y]]
[[Category: Malinauskas T]]
[[Category: Masiulis S]]
[[Category: Miehling J]]
[[Category: Miller KW]]
[[Category: Naydenova K]]
[[Category: Sente A]]
[[Category: Zhou X]]