Structural basis of the activation of a metabotropic GABA receptor

Shaye, Hamidreza; Ishchenko, Andrii; Lam, Jordy Homing; Han, Gye Won; Xue, Li; Rondard, Philippe; Pin, Jean-Philippe; Katritch, Vsevolod; Gati, Cornelius; Cherezov, Vadim

doi:10.1038/s41586-020-2408-4

Structural basis of the activation of a metabotropic GABA receptor

Journal Article · Wed Jun 17 00:00:00 EDT 2020 · Nature (London)

DOI:https://doi.org/10.1038/s41586-020-2408-4· OSTI ID:1637649

^[1]; ^[1]; Lam, Jordy Homing ^[1]; Han, Gye Won ^[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)

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 psychosis. 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 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 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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); USDOE Laboratory Directed Research and Development (LDRD) Program; Fondation pour la Recherche Médicale

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1637649

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7820 Vol. 584; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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