6x3z

From Proteopedia

(Difference between revisions)

Current revision

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA

Structural highlights

6x3z is a 9 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.23Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GBRB2_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.^[1] ^[2]

Publication Abstract from PubMed

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of gamma-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain(1-5). However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.

Shared structural mechanisms of general anaesthetics and benzodiazepines.,Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE Nature. 2020 Sep;585(7824):303-308. doi: 10.1038/s41586-020-2654-5. Epub 2020 Sep, 2. PMID:32879488^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS, Tsang SY, Xue H. Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS One. 2009 Sep 18;4(9):e6977. doi: 10.1371/journal.pone.0006977. PMID:19763268 doi:http://dx.doi.org/10.1371/journal.pone.0006977
↑ Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI, et al.. Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. Mol Pharmacol. 1993 Dec;44(6):1211-8. PMID:8264558
↑ Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE. Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature. 2020 Sep;585(7824):303-308. PMID:32879488 doi:10.1038/s41586-020-2654-5

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6x3z"

@@ Line 8: / Line 8: @@
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6x3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x3z OCA], [https://pdbe.org/6x3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x3z RCSB], [https://www.ebi.ac.uk/pdbsum/6x3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x3z ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[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.
 == Function ==
-[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/GBRB2_HUMAN GBRB2_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:19763268</ref> <ref>PMID:8264558</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

6x3z

From Proteopedia

Current revision

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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