6cdu

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==Crystal structure of a chimeric human alpha1GABAA receptor in complex with alphaxalone==
==Crystal structure of a chimeric human alpha1GABAA receptor in complex with alphaxalone==
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<StructureSection load='6cdu' size='340' side='right' caption='[[6cdu]], [[Resolution|resolution]] 3.45&Aring;' scene=''>
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<StructureSection load='6cdu' size='340' side='right'caption='[[6cdu]], [[Resolution|resolution]] 3.45&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6cdu]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CDU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CDU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6cdu]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Dickeya_dadantii_3937 Dickeya dadantii 3937] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CDU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CDU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EY4:(3a,5a)-3-Hydroxypregnane-11,20-dione'>EY4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.45&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GABRA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EY4:(3a,5a)-3-Hydroxypregnane-11,20-dione'>EY4</scene></td></tr>
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<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=6cdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cdu OCA], [http://pdbe.org/6cdu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cdu RCSB], [http://www.ebi.ac.uk/pdbsum/6cdu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cdu ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6cdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cdu OCA], [https://pdbe.org/6cdu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cdu RCSB], [https://www.ebi.ac.uk/pdbsum/6cdu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cdu ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[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.
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== Function ==
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[https://www.uniprot.org/uniprot/E0SJQ4_DICD3 E0SJQ4_DICD3] [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;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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A unique aspect of arrestin-3 is its ability to support both receptor-dependent and receptor-independent signaling. Here, we show that inositol hexakisphosphate (IP6) is a non-receptor activator of arrestin-3 and report the structure of IP6-activated arrestin-3 at 2.4-A resolution. IP6-activated arrestin-3 exhibits an inter-domain twist and a displaced C-tail, hallmarks of active arrestin. IP6 binds to the arrestin phosphate sensor, and is stabilized by trimerization. Analysis of the trimerization surface, which is also the receptor-binding surface, suggests a feature called the finger loop as a key region of the activation sensor. We show that finger loop helicity and flexibility may underlie coupling to hundreds of diverse receptors and also promote arrestin-3 activation by IP6. Importantly, we show that effector-binding sites on arrestins have distinct conformations in the basal and activated states, acting as switch regions. These switch regions may work with the inter-domain twist to initiate and direct arrestin-mediated signaling.
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Type A gamma-aminobutyric acid receptors (GABAARs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABAAR transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABAAR structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric alpha1GABAAR (ELIC-alpha1GABAAR). The chimera retains the functional and pharmacological properties of GABAARs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1-TM2 linker. The study provides a framework to discover new GABAAR modulators with therapeutic potential.
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Structural basis of arrestin-3 activation and signaling.,Chen Q, Perry NA, Vishnivetskiy SA, Berndt S, Gilbert NC, Zhuo Y, Singh PK, Tholen J, Ohi MD, Gurevich EV, Brautigam CA, Klug CS, Gurevich VV, Iverson TM Nat Commun. 2017 Nov 10;8(1):1427. doi: 10.1038/s41467-017-01218-8. PMID:29127291<ref>PMID:29127291</ref>
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Structural basis of neurosteroid anesthetic action on GABAA receptors.,Chen Q, Wells MM, Arjunan P, Tillman TS, Cohen AE, Xu Y, Tang P Nat Commun. 2018 Sep 28;9(1):3972. doi: 10.1038/s41467-018-06361-4. PMID:30266951<ref>PMID:30266951</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
<div class="pdbe-citations 6cdu" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6cdu" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[GABA receptor 3D structures|GABA receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Dickeya dadantii 3937]]
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[[Category: Arjunan, P]]
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[[Category: Homo sapiens]]
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[[Category: Chen, Q]]
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[[Category: Large Structures]]
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[[Category: Cohen, A E]]
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[[Category: Arjunan P]]
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[[Category: Tang, P]]
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[[Category: Chen Q]]
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[[Category: Xu, Y]]
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[[Category: Cohen AE]]
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[[Category: Alphaxalone]]
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[[Category: Tang P]]
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[[Category: Anesthetic]]
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[[Category: Xu Y]]
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[[Category: Gabaa receptor]]
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[[Category: Neurosteroid]]
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[[Category: Protein transport]]
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Current revision

Crystal structure of a chimeric human alpha1GABAA receptor in complex with alphaxalone

PDB ID 6cdu

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