4x5t

alpha 1 glycine receptor transmembrane structure fused to the extracellular domain of GLIC

spinqualitylabelsall models 4x5t, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4x5t is a 5 chain structure with sequence from Gloeobacter violaceus PCC 7421 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, CL, NI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GLRA1_HUMAN Defects in GLRA1 are the cause of hyperekplexia, hereditary, type 1 (HKPX1) [MIM: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. [:] Function 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).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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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