6UO9

Human metabotropic GABA(B) receptor bound to agonist SKF97541 in its intermediate state 2

Summary for 6UO9

• Entry DOI: 10.2210/pdb6uo9/pdb
• EMDB information: 20823
• Descriptor: Gamma-aminobutyric acid type B receptor subunit 1, Gamma-aminobutyric acid type B receptor subunit 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: g protein-coupled receptor, gaba, gabab, neurotransmitter, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 177515.50

Authors

Shaye, H.,Han, G.W.,Gati, C.,Cherezov, V. (deposition date: 2019-10-14, release date: 2020-06-10, Last modification date: 2024-11-06)

Primary citation

Shaye, H.,Ishchenko, A.,Lam, J.H.,Han, G.W.,Xue, L.,Rondard, P.,Pin, J.P.,Katritch, V.,Gati, C.,Cherezov, V.
Structural basis of the activation of a metabotropic GABA receptor.
Nature, 584:298-303, 2020

PubMed Abstract: Metabotropic γ-aminobutyric acid receptors (GABA) 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 psychosis. GABA 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 subunits. 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. 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.

PubMed: 32555460
DOI: 10.1038/s41586-020-2408-4

Experimental method

ELECTRON MICROSCOPY (4.8 Å)