PDBsum entry 6huj

Membrane protein

PDB id: 6huj

Contents

Protein chains

347 a.a.

336 a.a.

330 a.a.

121 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN-MAN-MAN

NAG-NAG-BMA-MAN-MAN-MAN ×2

NAG-NAG ×3

NAG-NAG-BMA-MAN-MAN

PIO ×2

RI5

ABU ×2

PDB id:

6huj

Name:

Membrane protein

Title:

Cryoem structure of human full-length heteromeric alpha1beta3gamma2l gaba(a)r in complex with picrotoxin, gaba and megabody mb38.

Structure:

Gamma-aminobutyric acid receptor subunit alpha-1,gamma- aminobutyric acid receptor subunit alpha-1. Chain: a, d. Synonym: gaba(a) receptor subunit alpha-1,gaba(a) receptor subunit alpha-1. Engineered: yes. Other_details: potential signal peptide: mkkspglsdy lwawtlflst ltgrsyg flag tag: dykddddk,potential signal peptide: mkkspglsdy lwawtlflst ltgrsyg flag tag: dykddddk.

Source:

Bos taurus, homo sapiens. Bovine, human. Organism_taxid: 9913, 9606. Gene: gabra1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293s. Expression_system_atcc_number: 3022. Homo sapiens.

Authors:

S.Masiulis,R.Desai,T.Uchanski,I.Serna Martin,D.Laverty,D.Karia, T.Malinauskas,Z.Jasenko,E.Pardon,A.Kotecha,J.Steyaert,K.W.Miller, A.R.Aricescu

Key ref:

S.Masiulis et al. (2019). GABA_A receptor signalling mechanisms revealed by structural pharmacology. Nature, 565, 454-459. PubMed id: 30602790 DOI: 10.1038/s41586-018-0832-5

Date:

08-Oct-18 Release date: 02-Jan-19

Protein chains

P08219  (GBRA1_BOVIN) -  Gamma-aminobutyric acid receptor subunit alpha-1 from Bos taurus

Seq: 456 a.a.

Struc: 347 a.a.

Protein chains

P14867  (GBRA1_HUMAN) -  Gamma-aminobutyric acid receptor subunit alpha-1 from Homo sapiens

Seq: 456 a.a.

Struc: 347 a.a.

Protein chains

P28472  (GBRB3_HUMAN) -  Gamma-aminobutyric acid receptor subunit beta-3 from Homo sapiens

Seq: 473 a.a.

Struc: 336 a.a.*

Protein chain

P18507  (GBRG2_HUMAN) -  Gamma-aminobutyric acid receptor subunit gamma-2 from Homo sapiens

Seq: 475 a.a.

Struc: 330 a.a.

Protein chain

No UniProt id for this chain

Struc: 121 a.a.

* PDB and UniProt seqs differ at 29 residue positions (black crosses)

DOI no: 10.1038/s41586-018-0832-5

Nature 565:454-459 (2019)

PubMed id: 30602790

GABA_A receptor signalling mechanisms revealed by structural pharmacology.

S.Masiulis, R.Desai, T.Uchański, I.Serna Martin, D.Laverty, D.Karia, T.Malinauskas, J.Zivanov, E.Pardon, A.Kotecha, J.Steyaert, K.W.Miller, A.R.Aricescu.

ABSTRACT

Type-A γ-aminobutyric (GABA_A) 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_A receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA_A 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_A 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_A receptor modulators.