Journal Article

Structural basis of the activation of a metabotropic GABA receptor

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

2020

Overview

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 1 . 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 2 . 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 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. Cryo-electron microscopy structures of apo, agonist- and positive allosteric modulator-bound forms of the GB1–GB2 heterodimer of the metabotropic γ-aminobutyric acid (GABA) receptor shed light on the activation mechanism of this receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 119/118 / 13/95 / 60 APPLIED LIFE SCIENCES / 631/45/612/194 / 631/535/1258/1259 / 82/1 / 82/16 / 82/29 / 82/80 / 82/83 / Activation / Addictions / Agonists / Allosteric properties / Allosteric Regulation - drug effects / Apoproteins - chemistry / Apoproteins - metabolism / Apoproteins - ultrastructure / Binding / Binding Sites - drug effects / Central nervous system / Cryoelectron Microscopy / Crystal structure / Datasets / Dimerization / Dionaea / Domains / Electron microscopy / G protein-coupled receptors / GABA-B Receptor Agonists - chemistry / GABA-B Receptor Agonists - metabolism / GABA-B Receptor Agonists - pharmacology / Humanities and Social Sciences / Humans / Ligands / Metabotropic receptors / Microscopy / Models, Molecular / multidisciplinary / Nervous system / Neurosciences / Neurotransmitters / Plants (botany) / Protein Domains - drug effects / Protein Multimerization - drug effects / Proteins / Receptors / Receptors, GABA-B - chemistry / Receptors, GABA-B - metabolism / Receptors, GABA-B - ultrastructure / Science / Science (multidisciplinary) / Signal Transduction / Structure-Activity Relationship / Transmembrane domains / γ-Aminobutyric acid B receptors