6hug

CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with picrotoxin and megabody Mb38.CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with picrotoxin and megabody Mb38.

6hug, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Structural highlights 6hug is a 6 chain structure with sequence from Bos taurus, Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: Experimental data: Check Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBRA1_BOVIN 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. Publication Abstract from PubMed Type-A gamma-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human alpha1beta3gamma2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (gamma-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators. GABAA receptor signalling mechanisms revealed by structural pharmacology.,Masiulis S, Desai R, Uchanski T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR Nature. 2019 Jan 2. pii: 10.1038/s41586-018-0832-5. doi:, 10.1038/s41586-018-0832-5. PMID:30602790 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also GABA receptor 3D structures