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Structure paper

TitleGABA receptor signalling mechanisms revealed by structural pharmacology.
Journal, issue, pagesNature, Vol. 565, Issue 7740, Page 454-459, Year 2019
Publish dateJan 2, 2019
AuthorsSimonas Masiulis / Rooma Desai / Tomasz Uchański / Itziar Serna Martin / Duncan Laverty / Dimple Karia / Tomas Malinauskas / Jasenko Zivanov / Els Pardon / Abhay Kotecha / Jan Steyaert / Keith W Miller / A Radu Aricescu /
PubMed AbstractType-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the ...Type-A γ-aminobutyric (GABA) 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 GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-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 GABA 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 GABA receptor modulators.
External linksNature / PubMed:30602790 / PubMed Central
MethodsEM (single particle)
Resolution3.04 - 3.69 Å
Structure data

0275

6hug

EMDB-0275, PDB-6hug:
CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with picrotoxin and megabody Mb38.
Method: EM (single particle) / Resolution: 3.1 Å

0279

6huj

EMDB-0279, PDB-6huj:
CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with picrotoxin, GABA and megabody Mb38.
Method: EM (single particle) / Resolution: 3.04 Å

0280

6huk

EMDB-0280, PDB-6huk:
CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with bicuculline and megabody Mb38.
Method: EM (single particle) / Resolution: 3.69 Å

0282

6huo

EMDB-0282, PDB-6huo:
CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with alprazolam (Xanax), GABA and megabody Mb38.
Method: EM (single particle) / Resolution: 3.26 Å

0283

6hup

EMDB-0283, PDB-6hup:
CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with diazepam (Valium), GABA and megabody Mb38.
Method: EM (single particle) / Resolution: 3.58 Å

Chemicals

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-RI5:
(1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-2-yl)hexahydro-3,6-methano-1,5,7-trioxacyclopenta[ij]c / toxin*YM / Picrotoxin

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM / Γ-Aminobutyric acid

ChemComp-H0Z:
bicuculline methochloride / antagonist, alkaloid*YM / Bicuculline

ChemComp-08H:
8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine / Alprazolam

ChemComp-DZP:
7-CHLORO-1-METHYL-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE / Diazepam

Source
  • homo sapiens (human)
  • lama glama (llama)
  • bos taurus (cattle)
KeywordsMEMBRANE PROTEIN / GABAAR / PTX / Membrane / Channel / Nanobody / Megabody / Cys-loop / PLGIC / Inhibition / Signalling / CNS / Neurons / Chloride / Ion / GABA / Picrotoxin / BCC / Bicuculline / Antagonist / Cys-loop receptor

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