PDBsum entry 6uo9

Membrane protein

PDB id: 6uo9

Contents

Protein chains

675 a.a.

690 a.a.

Ligands

NAG-NAG ×4

NAG-NAG-BMA

QD7

NAG ×2

PDB id:

6uo9

Name:

Membrane protein

Title:

Human metabotropic gaba(b) receptor bound to agonist skf97541 in its intermediate state 2

Structure:

Gamma-aminobutyric acid type b receptor subunit 1. Chain: a. Synonym: gb1. Engineered: yes. Gamma-aminobutyric acid type b receptor subunit 2. Chain: b. Synonym: gb2,g-protein coupled receptor 51,hg20. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gabbr1, gprc3a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: gabbr2, gpr51, gprc3b. Expression_system_taxid: 7108

Authors:

H.Shaye,G.W.Han,C.Gati,V.Cherezov

Key ref:

H.Shaye et al. (2020). Structural basis of the activation of a metabotropic GABA receptor. Nature, 584, 298-303. PubMed id: 32555460 DOI: 10.1038/s41586-020-2408-4

Date:

14-Oct-19 Release date: 10-Jun-20

Protein chain

Q9UBS5  (GABR1_HUMAN) -  Gamma-aminobutyric acid type B receptor subunit 1 from Homo sapiens

Seq: 961 a.a.

Struc: 675 a.a.

Protein chain

O75899  (GABR2_HUMAN) -  Gamma-aminobutyric acid type B receptor subunit 2 from Homo sapiens

Seq: 941 a.a.

Struc: 690 a.a.

DOI no: 10.1038/s41586-020-2408-4

Nature 584:298-303 (2020)

PubMed id: 32555460

Structural basis of the activation of a metabotropic GABA receptor.

H.Shaye, A.Ishchenko, J.H.Lam, G.W.Han, L.Xue, P.Rondard, J.P.Pin, V.Katritch, C.Gati, V.Cherezov.

ABSTRACT

Metabotropic γ-aminobutyric acid receptors (GABA_B) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis¹. GABA_B belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits². Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABA_B. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.