National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM127086
United States
Department of Energy (DOE, United States)
DE-AC02-76SF00515
United States
Citation
Journal: Nature / Year: 2020 Title: Structural basis of the activation of a metabotropic GABA receptor. Authors: Hamidreza Shaye / Andrii Ishchenko / Jordy Homing Lam / Gye Won Han / Li Xue / Philippe Rondard / Jean-Philippe Pin / Vsevolod Katritch / Cornelius Gati / Vadim Cherezov / 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 ...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.
History
Deposition
Jan 16, 2020
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Header (metadata) release
Jan 29, 2020
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Map release
Jun 10, 2020
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Update
Nov 25, 2020
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Current status
Nov 25, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 5947 / Average exposure time: 0.2 sec. / Average electron dose: 1.3 e/Å2
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