View source for 6i53


==Cryo-EM structure of the human synaptic alpha1-beta3-gamma2 GABAA receptor in complex with Megabody38 in a lipid nanodisc==
<SX load='6i53' size='340' side='right' viewer='molstar' caption='[[6i53]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6i53]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Camelus_glama Camelus glama] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I53 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I53 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=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>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GABRB3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GABRA1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GABRG2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6i53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i53 OCA], [https://pdbe.org/6i53 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i53 RCSB], [https://www.ebi.ac.uk/pdbsum/6i53 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i53 ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/GBRB3_HUMAN GBRB3_HUMAN]] Autism;Childhood absence epilepsy. Disease susceptibility is associated with variations affecting the gene represented in this entry. [[https://www.uniprot.org/uniprot/GBRG2_HUMAN GBRG2_HUMAN]] Childhood absence epilepsy;Dravet syndrome;Generalized epilepsy with febrile seizures-plus. 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.  The disease is caused by mutations affecting the gene represented in this entry. [[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/GBRB3_HUMAN GBRB3_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. [[https://www.uniprot.org/uniprot/GBRG2_HUMAN GBRG2_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.<ref>PMID:2538761</ref>  [[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). 
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== Publication Abstract from PubMed ==
Type A gamma-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system(1,2). Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia(3,4). Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the alpha1beta2/3gamma2 GABAA receptors(5). The beta3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in beta1-beta3 triple knockout neurons(6). So far, efforts to generate accurate structural models for heteromeric GABAA receptors have been hampered by the use of engineered receptors and the presence of detergents(7-9). Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations(8,9); however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor(10,11), the large body of structural work on homologous homopentameric receptor variants(12) and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human alpha1beta3gamma2L-a major synaptic GABAA receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABAA receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of alpha1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABAA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

Cryo-EM structure of the human alpha1beta3gamma2 GABAA receptor in a lipid bilayer.,Laverty D, Desai R, Uchanski T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR Nature. 2019 Jan 2. pii: 10.1038/s41586-018-0833-4. doi:, 10.1038/s41586-018-0833-4. PMID:30602789<ref>PMID:30602789</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 6i53" style="background-color:#fffaf0;"></div>

==See Also==
*[[GABA receptor 3D structures|GABA receptor 3D structures]]
== References ==
<references/>
__TOC__
</SX>
[[Category: Camelus glama]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Aricescu, A R]]
[[Category: Desai, R]]
[[Category: Laverty, D]]
[[Category: Malinauskas, T]]
[[Category: Masiulis, S]]
[[Category: Miller, K W]]
[[Category: Pardon, E]]
[[Category: Steyaert, J]]
[[Category: Uchanski, T]]
[[Category: Wojciech, J S]]
[[Category: Zivanov, J]]
[[Category: Ligand gated ion channel cys-loop receptor gaba-a receptor]]
[[Category: Transport protein]]