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.
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Data availability
The cryo-EM density maps and corresponding coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and the PDB, respectively, under the following accession codes: EMD-20822 and 6UO8 (SKF97541- and GS39783-bound GABAB), EMD-20823 and 6UO9 (SKF97541-bound GABAB, int-2 state), EMD-20824 and 6UOA (SKF97541-bound GABAB, int-1 state), and EMD-21219 and 6VJM (apo GABAB).
Source data are provided with this paper. Supplementary Figure 1 contains the uncropped gel shown in Extended Data Fig. 1f. All other data are available from the authors on reasonable request.
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Acknowledgements
We thank K. Villers, C. Hanson, F. Nasertorabi, J. Velasquez and M. Barekatain for technical support; S. Roux for the help with collecting functional data; E. Montabana for microscope support; Y.-T. Li and N. Patel for support with computing resources; and Y. Kadyshevskaya for help with illustrations. This research was supported by the National Institutes of Health (NIH) grant R35 GM127086 (V.C.), by the Department of Energy, Laboratory Directed Research and Development program at SLAC National Accelerator Laboratory, under contract DE-AC02-76SF00515, and by the Fondation pour la Recherche Médicale (DEQ20170336747, to J.-P.P.). We acknowledge the SLAC-Stanford Cryo-EM center (SLAC National Accelerator Laboratory) for microscope time. Functional experiments were performed at the ARPEGE (Pharmacology Screening-Interactome) facility, Institut de Génomique Fonctionnelle. We acknowledge Google Cloud Platform credits and USC High Performance Computing Center for computer resources used in molecular dynamics simulations.
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Contributions
H.S. expressed and purified GABAB heterodimers for cryo-EM data collection. A.I. helped with the development of protocols for receptor expression and purification. C.G. performed cryo-EM sample preparation, data collection and image processing. L.X. performed ligand-binding and functional experiments. G.W.H. helped with the structure refinement and quality control. J.H.L, and V.K. performed molecular dynamics and ANM modelling. P.R., J.-P.P., J.H.L. and V.K. analysed data. H.S., C.G. and V.C. conceived the project, analysed data, and wrote the manuscript with contributions from all authors. V.C. supervised the project.
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Extended data figures and tables
Extended Data Fig. 1 Expression, characterization and purification of GABAB.
a, b, Cell surface expression of Halo–GB1 (a) and SNAP–GB2 (b), transfected alone or cotransfected with the second subunit, measured by the fluorescence emission of the Lumi4-Tb bound to the Halo (a) or SNAP tag (b). Values are normalized by the wild-type GB1 cotransfected with wild-type GB2 (purple bar) and shown as mean ± s.d. of three biologically independent experiments. GABAB constructs for cryo-EM are expressed and function similarly to the wild-type receptor. c, d, Positive allosteric effect of GS39783 (5 μM) on IP1 accumulation in cells expressing wild-type or cryo-EM constructs of GABAB heterodimers and activated either by GABA (c) or SKF97541 (d). Data are normalized by the wild-type response in absence of GS39783 (control) and shown as mean ± s.e.m. of three biologically independent experiments (4 for wild type). e, Representative SEC profile of apo GABAB in digitonin micelles. Dimeric fractions were pooled, supplemented with ligand and concentrated for cryo-EM imaging. f, Coomassie stained SDS–PAGE profile shows two distinct bands for GB1 (86 kDa) and GB2 (88 kDa). For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 2 Cryo-EM data processing for SKF97541-bound GABAB.
a, Single-particle cryo-EM data processing scheme using RELION and cryoSPARC. b, Representative micrograph showing picked particles. c, Representative 2D class averages. d, Angular distribution of particles included in the final cryo-EM reconstruction for the int-1 state. e, The same as d but for the int-2 state. f, g, Density maps for int-1 (f) and int-2 (g) states coloured by local resolution, showing higher resolution at the VFT interface.
Extended Data Fig. 3 Cryo-EM map quality.
a–d, Representative densities and fitted atomic models are shown for GABAB in the inactive apo state (a), active agonist- and PAM-bound state (b), and two intermediate int-1 (c) and int-2 states (d).
Extended Data Fig. 4 Cryo-EM data processing for SKF97541- and GS39783-bound GABAB.
a, Single-particle cryo-EM data processing scheme using cryoSPARC. b, Micrograph showing picked particles. c, Representative 2D class averages show distinct secondary structure features. d, Particle angular distribution of the final cryo-EM reconstruction. e, Structural model shown in cartoon representation and coloured by the B-factors. f, Density map coloured by local resolution, showing higher resolution at the interface between GB1 and GB2. g, The heterodimer interface includes both LB1 and LB2, as well as TM6, with a total interface area of 1,930 Å2. Residues involved in dimerization contacts are coloured in purple.
Extended Data Fig. 5 Cryo-EM data processing for apo GABAB.
a, Single-particle cryo-EM data processing scheme using cryoSPARC. b, Micrograph showing picked particles. c, Representative 2D class averages show distinct secondary structure features. d, Particle angular distribution of the final cryo-EM reconstruction. e, Structural model shown in cartoon representation and coloured by the B-factors. f, Density map coloured by local resolution, showing higher resolution at the interface of GB1 and GB2. g, Gold-standard FSC curves from cryoSPARC. h, Map-to-model FSC curve between each refined model and the corresponding sharpened electron potential maps. i, GB1 and GB2 interact through LB1s and intracellular tips of TM3 and TM5, with a total interface area of 963 Å2. Residues involved in dimerization contacts are coloured in purple.
Extended Data Fig. 6 Molecular dynamics simulations of inactive (apo) and active (agonist- and PAM-bound) states.
a, VFT fluctuations in the inactive state are illustrated by comparing molecular dynamics snapshots at 500 ns for all 5 trajectories (cartoon, purple for α-helices and yellow for β-strands) against the cryo-EM structure (grey surface). Cyan spheres indicate nitrogen of hydrophilic heads of the POPC lipid bilayer. Asterisk corresponds to trajectory 1. b, Traces of Cα r.m.s.d. for different domains in trajectory 1. The structures in the trajectory were aligned by TMDs against the cryo-EM structure. c, Distribution of distances for ionic interactions between TM3 and TM5 at the intracellular side of the apo GABAB, as observed in molecular dynamics simulations. d, e, Membrane-coupled ANM analysis of the inactive (d)- and active (e)-state cryo-EM structures. Eigenvectors of the slowest mode are drawn on every eighth Cα as magenta arrows. In the inset heat map, overall dynamics of the protein as observed in molecular dynamics simulations are compared against that predicted from ANM analysis on electron microscopy structures; correlations between eigenvectors of the ten slowest ANM modes and the principal components of Cα motions in molecular dynamics simulations are calculated, showing concurrence between the two. f, Distance plots as observed in agonist- and PAM-bound trajectories for interactions between SKF97541 (SKF) and various contact residues in the GB1 pocket (left column), interactions between GS39783 (PAM) and its contact residues at the TMD interface (right column, rows 1–3) and interactions between GB1 and GB2 residues (right column, rows 4 and 5). g, h, Traces of Cα r.m.s.d. on the overall structure for individual molecular dynamics trajectories (green) and plots of root mean square fluctuations (r.m.s.f.) per residue in GB1 (blue) and GB2 (yellow) subunits as observed in molecular dynamics simulations for inactive (g) and active (h) states. i, j, Stacked snapshots of GS39783 (i) and SKF97541 (j) binding site for one of the trajectories, taken every 50 ns and spanning 500 ns. In traces of Cα r.m.s.d. (b, g, h), data (solid line) are presented as an average within a sliding window of 500 ps; shading refers to 95% confidence interval (n = 500). In plots of r.m.s.f. (g, h), data (solid line) are shown as an average of 5 independent trajectories at each residue position; shading refers to 95% confidence interval (n = 5).
Extended Data Fig. 7 Comparisons with previous crystal structures and additional details of activation-related transitions in GABAB.
a, Comparison of the VFTs between the apo cryo-EM structure (teal) and the apo crystal structure (PDB 4MQE, grey). b, Comparison of the VFTs between the active agonist- and PAM-bound cryo-EM structure (orange) and the GABA-bound crystal structure (PDB 4MS3, grey). c, Comparison between GB1 and GB2 TMDs in the inactive apo state demonstrates no substantial difference between the subunits. d, Comparison between GB1 and GB2 TMDs in the active agonist- and PAM-bound state illustrates the differences between the subunits upon activation. e, The TMD of GB1 remains unchanged between the int-2 and the active agonist- and PAM-bound states. f, Shifts of TM3 and TM5 at the intracellular side of the TMD of GB2 between the int-2 and active states open up a cleft for the engagement of a G protein.
Extended Data Fig. 8 Effects of a PAM on the orthosteric ligand binding in the site-1 and -2 mutants of GABAB.
a, Displacement of the CGP54626-DY647 by GABA in intact cells expressing the wild-type GABAB receptor in the absence (blue) or presence of 5 μM (red), 10 μM (orange) or 20 μM (sand) GS39783. b, Cell-surface expression of site-1 and -2 mutants, measured by cotransfecting Halo–GB1 with GB2 and recording fluorescence emission of Halo–Lumi4-Tb. Data are normalized by the wild-type expression and shown as mean ± s.d. The numbers of biologically independent experiments are shown in parentheses. c, pKi values for GABA were determined from displacement of CGP54626-DY647 binding in intact cells expressing the indicated subunit combinations in the absence or presence of 1 μM or 5 μM GS39783. Values are mean ± s.e.m. of 4 (10 for wild type) biologically independent experiments. Data are analysed using one-way ANOVA with Dunnett’s multiple comparison test to determine significance (compared with no GS39783 for the same combined subunits), with ****P ≤ 0.0001, ***P ≤ 0.001, *P ≤ 0.01 and NS (not significant) P > 0.05. For 1 μM (5 μM) GS39783, P = 0.0030 (0.0045) for GB2(R556A), 0.0205 (0.0157) for GB2(H647A), 0.0084 (0.0009) for GB2(L657A), 0.0436 (0.0003) for GB2(F711A), 0.0013 (0.0053) for GB2(R714A), 0.0373 (0.0056) for GB2(Q720A), and 0.0735 (0.0019) for GB2(SFR-AAA). GB2(SFR-AAA) refers to a triple mutant (S710A/F711A/R714A) of GB2. d, e, Displacement of the CGP54626-DY647 by GABA in intact cells expressing the indicated mutants in site 1 (d) and site 2 (e), in the absence or presence of the indicated concentrations of GS39783 as in a. Data are normalized by the signal in absence of GS39783 and shown as mean ± s.e.m. of three biologically independent experiments.
Extended Data Fig. 9 The effects of a PAM on signalling of the site-1 and -2 mutants of GABAB.
a, IP1 production induced by 10 μM GS39783 in intact cells expressing the indicated site-1 GB2 mutants co-expressed with the wild-type GB1. Data are normalized by the GABA response and shown as mean ± s.d. of 7 (10 for wild type) biologically independent experiments. Data are analysed using one-way ANOVA with Dunnett’s multiple comparison test to determine significance (compared with wild type), with P = 0.9998 for GB2(R556A), 0.9999 for GB2(H647A), 0.9907 for GB2(L657A), 0.9995 for GB1(F711A), 0.9997 for GB2(R714A), 0.9996 for GB2(Q720A), and 0.2807 for GB2(SFR-AAA). b–d, IP1 production induced by GABA (blue) or GS39783 (red) in intact cells expressing the wild-type receptor (b) or the indicated mutant of the site 1 (c) or site 2 (d). Data are normalized by the GABA response and shown as mean ± s.e.m. of four biologically independent experiments.
Supplementary information
Supplementary Figure 1
This file contains the uncropped gel used in Extended Data Fig. 1f.
Video 1
: Conformational transitions related to GABAB activation Overview of the modeled activation pathway as illustrated transitions between the four obtained models of GABAB heterodimers. Morphs were calculated between inactive apo, agonist-bound int-1 and int-2, to the agonist/PAM-bound structure, with a sequential alignment of the entire receptor.
Video 2
: Details of SKF97541 binding Rocking video (90°) around the electron potential map of the agonist SKF97541 in the binding pocket of the agonist/PAM-bound GABAB structure, depicted in Fig. 3c.
Video 3
: Details of GS39783 binding Rocking video (60°) around the electron potential map of PAM GS39783 in the binding pocket at the dimer interface of the agonist/PAM-bound GABAB structure, depicted in Fig. 3d.
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Shaye, H., Ishchenko, A., Lam, J.H. et al. Structural basis of the activation of a metabotropic GABA receptor. Nature 584, 298–303 (2020). https://doi.org/10.1038/s41586-020-2408-4
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DOI: https://doi.org/10.1038/s41586-020-2408-4
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