6huk | pdb_00006huk

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

Loading... Status: waiting for Mol* initialization Structural highlights 6huk 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 3.69Å Ligands: BMA, H0Z, MAN, NAG, PIO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GBRB3_HUMAN Autism;Childhood absence epilepsy. Disease susceptibility is associated with variations affecting the gene represented in this entry. Function GBRB3_HUMAN GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral 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

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