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| | ==GLIC-GABAAR alpha1 chimera crystallized in complex with THDOC at pH4.5== | | ==GLIC-GABAAR alpha1 chimera crystallized in complex with THDOC at pH4.5== |
| - | <StructureSection load='5osb' size='340' side='right' caption='[[5osb]], [[Resolution|resolution]] 3.80Å' scene=''> | + | <StructureSection load='5osb' size='340' side='right'caption='[[5osb]], [[Resolution|resolution]] 3.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5osb]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OSB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OSB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5osb]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Gloeobacter_violaceus_PCC_7421 Gloeobacter violaceus PCC 7421] 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=5OSB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OSB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A8Z:Tetrahydrodeoxycorticosterone'>A8Z</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.8Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Gabra1, Gabra-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A8Z:Tetrahydrodeoxycorticosterone'>A8Z</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5osb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5osb OCA], [http://pdbe.org/5osb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5osb RCSB], [http://www.ebi.ac.uk/pdbsum/5osb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5osb 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=5osb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5osb OCA], [https://pdbe.org/5osb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5osb RCSB], [https://www.ebi.ac.uk/pdbsum/5osb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5osb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GLIC_GLOVI GLIC_GLOVI]] Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.<ref>PMID:17167423</ref> | + | [https://www.uniprot.org/uniprot/GBRA1_MOUSE GBRA1_MOUSE] Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:27129275). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:27129275). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (PubMed:27129275). The alpha1/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:27129275). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (PubMed:25348603). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).[UniProtKB:P62813]<ref>PMID:25348603</ref> <ref>PMID:27129275</ref> [https://www.uniprot.org/uniprot/GLIC_GLOVI GLIC_GLOVI] Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.<ref>PMID:17167423</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5osb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5osb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ion channels 3D structures|Ion channels 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Gloeobacter violaceus PCC 7421]] |
| - | [[Category: Gold, M G]] | + | [[Category: Large Structures]] |
| - | [[Category: Laverty, D C]] | + | [[Category: Mus musculus]] |
| - | [[Category: Smart, T G]] | + | [[Category: Gold MG]] |
| - | [[Category: Gabaa-receptor ion channel ion transport extracellular ligand gated ion channel]] | + | [[Category: Laverty DC]] |
| - | [[Category: Transport protein]] | + | [[Category: Smart TG]] |
| Structural highlights
Function
GBRA1_MOUSE Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:27129275). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:27129275). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (PubMed:27129275). The alpha1/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic activity (PubMed:27129275). GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (PubMed:25348603). Functions also as histamine receptor and mediates cellular responses to histamine (By similarity).[UniProtKB:P62813][1] [2] GLIC_GLOVI Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.[3]
Publication Abstract from PubMed
gamma-Aminobutyric acid receptors (GABAARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABAARs is the alpha subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAAR function requires high-resolution structures. Here we present the first atomic structures of a GABAAR chimera at 2.8-A resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the alpha-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABAARs in neurological disorders.
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.,Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG Nat Struct Mol Biol. 2017 Oct 2. doi: 10.1038/nsmb.3477. PMID:28967882[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Swanson AM, Allen AG, Shapiro LP, Gourley SL. GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Neuropsychopharmacology. 2015 Mar;40(4):1027-36. PMID:25348603 doi:10.1038/npp.2014.292
- ↑ Brown LE, Nicholson MW, Arama JE, Mercer A, Thomson AM, Jovanovic JN. γ-Aminobutyric Acid Type A (GABAA) Receptor Subunits Play a Direct Structural Role in Synaptic Contact Formation via Their N-terminal Extracellular Domains. J Biol Chem. 2016 Jul 1;291(27):13926-13942. PMID:27129275 doi:10.1074/jbc.M116.714790
- ↑ Bocquet N, Prado de Carvalho L, Cartaud J, Neyton J, Le Poupon C, Taly A, Grutter T, Changeux JP, Corringer PJ. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature. 2007 Jan 4;445(7123):116-9. Epub 2006 Dec 10. PMID:17167423 doi:10.1038/nature05371
- ↑ Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat Struct Mol Biol. 2017 Oct 2. doi: 10.1038/nsmb.3477. PMID:28967882 doi:http://dx.doi.org/10.1038/nsmb.3477
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