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==Cryo-EM structure of human full-length extrasynaptic alpha4beta3delta GABA(A)R in complex with GABA, histamine and nanobody Nb25==
<StructureSection load='7qn7' size='340' side='right'caption='[[7qn7]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qn7]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QN7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QN7 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]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABU:GAMMA-AMINO-BUTANOIC+ACID'>ABU</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=D10:DECANE'>D10</scene>, <scene name='pdbligand=HSM:HISTAMINE'>HSM</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PX6:1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE'>PX6</scene>, <scene name='pdbligand=R16:HEXADECANE'>R16</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=7qn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qn7 OCA], [https://pdbe.org/7qn7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qn7 RCSB], [https://www.ebi.ac.uk/pdbsum/7qn7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qn7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GBRA4_HUMAN GBRA4_HUMAN] GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
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== 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>
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<div class="pdbe-citations 7qn7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[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]]