EMD-20822
Human metabotropic GABA(B) receptor bound to agonist SKF97541 and positive allosteric modulator GS39783.
EMD-20822
Single-particle3.63 Å
Deposition: 14/10/2019
Map released: 10/06/2020
Last modified: 30/10/2024
Sample Organism:
Homo sapiens
Sample: GABA(B) receptor bound to agonist and PAM
Fitted models: 6uo8 (Avg. Q-score: 0.447)
Deposition Authors: Shaye H , Han GW
Sample: GABA(B) receptor bound to agonist and PAM
Fitted models: 6uo8 (Avg. Q-score: 0.447)
Deposition Authors: Shaye H , Han GW
Structural basis of the activation of a metabotropic GABA receptor.
Shaye H ,
Ishchenko A ,
Lam JH ,
Han GW ,
Xue L ,
Rondard P ,
Pin JP ,
Katritch V ,
Gati C ,
Cherezov V
(2020) Nature , 584 , 298 - 303
(2020) Nature , 584 , 298 - 303
Abstract:
Metabotropic γ-aminobutyric acid receptors (GABAB) 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. GABAB 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 GABAB. 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.
Metabotropic γ-aminobutyric acid receptors (GABAB) 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. GABAB 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 GABAB. 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.