View source for 4x5t


==alpha 1 glycine receptor transmembrane structure fused to the extracellular domain of GLIC==
<StructureSection load='4x5t' size='340' side='right'caption='[[4x5t]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4x5t]] 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/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X5T FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=4x5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x5t OCA], [https://pdbe.org/4x5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x5t RCSB], [https://www.ebi.ac.uk/pdbsum/4x5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x5t ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GLRA1_HUMAN GLRA1_HUMAN] Defects in GLRA1 are the cause of hyperekplexia, hereditary, type 1 (HKPX1) [MIM:[https://omim.org/entry/149400 149400]. A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli.<ref>PMID:8298642</ref> [:]<ref>PMID:7925268</ref> <ref>PMID:7981700</ref> <ref>PMID:7881416</ref> <ref>PMID:7611730</ref> <ref>PMID:8571969</ref> <ref>PMID:8733061</ref> <ref>PMID:9067762</ref> <ref>PMID:10514101</ref> <ref>PMID:9920650</ref> 
== Function ==
[https://www.uniprot.org/uniprot/GLRA1_HUMAN GLRA1_HUMAN] The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).[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;">
== Publication Abstract from PubMed ==
The glycine receptor (GlyR) is a pentameric ligand-gated ion channel (pLGIC) mediating inhibitory transmission in the nervous system. Its transmembrane domain (TMD) is the target of allosteric modulators such as general anesthetics and ethanol and is a major locus for hyperekplexic congenital mutations altering the allosteric transitions of activation or desensitization. We previously showed that the TMD of the human alpha1GlyR could be fused to the extracellular domain of GLIC, a bacterial pLGIC, to form a functional chimera called Lily. Here, we overexpress Lily in Schneider 2 insect cells and solve its structure by X-ray crystallography at 3.5 A resolution. The TMD of the alpha1GlyR adopts a closed-channel conformation involving a single ring of hydrophobic residues at the center of the pore. Electrophysiological recordings show that the phenotypes of key allosteric mutations of the alpha1GlyR, scattered all along the pore, are qualitatively preserved in this chimera, including those that confer decreased sensitivity to agonists, constitutive activity, decreased activation kinetics, or increased desensitization kinetics. Combined structural and functional data indicate a pore-opening mechanism for the alpha1GlyR, suggesting a structural explanation for the effect of some key hyperekplexic allosteric mutations. The first X-ray structure of the TMD of the alpha1GlyR solved here using GLIC as a scaffold paves the way for mechanistic investigation and design of allosteric modulators of a human receptor.

Allosteric and hyperekplexic mutant phenotypes investigated on an alpha1 glycine receptor transmembrane structure.,Moraga-Cid G, Sauguet L, Huon C, Malherbe L, Girard-Blanc C, Petres S, Murail S, Taly A, Baaden M, Delarue M, Corringer PJ Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2865-70. doi:, 10.1073/pnas.1417864112. Epub 2015 Feb 17. PMID:25730860<ref>PMID:25730860</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4x5t" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Gloeobacter violaceus PCC 7421]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Corringer PJ]]
[[Category: Delarue M]]
[[Category: Huon C]]
[[Category: Sauguet L]]