Structural basis of the activation of a metabotropic GABA receptor
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 psychosis. 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 subunits. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. In this paper 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 positivemore »
- Authors:
-
[1];
[1];
[2];
[2];
[2];
[1];
[3];
[1]
- Univ. of Southern California, Los Angeles, CA (United States)
- Univ. de Montpellier (France)
- SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE Laboratory Directed Research and Development (LDRD) Program; Fondation pour la Recherche Médicale
- OSTI Identifier:
- 1637649
- Grant/Contract Number:
- AC02-76SF00515; R35 GM127086
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 584; Journal Issue: 7820; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Cryoelectron microscopy; G protein-coupled receptors
Citation Formats
Shaye, Hamidreza, Ishchenko, Andrii, Lam, Jordy Homing, Han, Gye Won, Xue, Li, Rondard, Philippe, Pin, Jean-Philippe, Katritch, Vsevolod, Gati, Cornelius, and Cherezov, Vadim. Structural basis of the activation of a metabotropic GABA receptor. United States: N. p., 2020.
Web. doi:10.1038/s41586-020-2408-4.
Shaye, Hamidreza, Ishchenko, Andrii, Lam, Jordy Homing, Han, Gye Won, Xue, Li, Rondard, Philippe, Pin, Jean-Philippe, Katritch, Vsevolod, Gati, Cornelius, & Cherezov, Vadim. Structural basis of the activation of a metabotropic GABA receptor. United States. https://doi.org/10.1038/s41586-020-2408-4
Shaye, Hamidreza, Ishchenko, Andrii, Lam, Jordy Homing, Han, Gye Won, Xue, Li, Rondard, Philippe, Pin, Jean-Philippe, Katritch, Vsevolod, Gati, Cornelius, and Cherezov, Vadim. Wed .
"Structural basis of the activation of a metabotropic GABA receptor". United States. https://doi.org/10.1038/s41586-020-2408-4. https://www.osti.gov/servlets/purl/1637649.
@article{osti_1637649,
title = {Structural basis of the activation of a metabotropic GABA receptor},
author = {Shaye, Hamidreza and Ishchenko, Andrii and Lam, Jordy Homing and Han, Gye Won and Xue, Li and Rondard, Philippe and Pin, Jean-Philippe and Katritch, Vsevolod and Gati, Cornelius and Cherezov, Vadim},
abstractNote = {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 psychosis. 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 subunits. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. In this paper 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.},
doi = {10.1038/s41586-020-2408-4},
journal = {Nature (London)},
number = 7820,
volume = 584,
place = {United States},
year = {Wed Jun 17 00:00:00 EDT 2020},
month = {Wed Jun 17 00:00:00 EDT 2020}
}
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