Structural mechanism of glutamate receptor activation and desensitization

Abstract

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the vertebrate brain. To gain a better understanding of how structural changes gate ion flux across the membrane, we trapped rat AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional states and analysed the resulting structures using cryo-electron microscopy. We show that transition to the active state involves a ‘corkscrew’ motion of the receptor assembly, driven by closure of the ligand-binding domain. Desensitization is accompanied by disruption of the amino-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry transition in the ligand-binding domains in both subtypes. The 7.6 Å structure of a desensitized kainate receptor shows how these changes accommodate channel closing. These findings integrate previous physiological, biochemical and structural analyses of glutamate receptors and provide a molecular explanation for key steps in receptor gating.

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Figure 1: GluA2 purification imaging and the antagonist-bound closed state structure.
Figure 2: Structural changes accompanying opening of GluA2.
Figure 3: Conformational ensemble of desensitized GluA2.
Figure 4: GluK2 receptor desensitization.
Figure 5: Unified view of glutamate receptor gating cycle.

Accession codes

Primary accessions

Electron Microscopy Data Bank

Protein Data Bank

Data deposits

Cryo-EM density maps for GluA2em with ZK200775, GluA2em with LY451646 and glutamate, GluA2em with quisqualate classes 1–3, GluA2em with quisqualate and LY451646, and GluK2 with 2S,4R-4-methylglutamate, have been deposited in the EM Data Bank under accession codes 2680, 2684, 2686, 2687, 2688, 2689 and 2685. Atomic coordinates for molecular models of GluA2em with ZK200775, GluA2em with LY451646 and glutamate, GluA2em with LY451646 and quisqualate, and of GluK2 with 2S,4R-4-methylglutamate (with separate models for the ATD/LBD and transmembrane domain) have been deposited in the Protein Data Bank under accession codes 4UQJ, 4UQ6, 4UQK and 4UQQ.

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Acknowledgements

This work was supported by the intramural programs of the NCI, and NICHD, NIH, the IATAP program at NIH and the NIH-FEI Living Lab for Structural Biology. We thank D. Bleakman, Eli Lilly and Company for the gift of LY451646, Y. J. Eun for discussions on preparation of cryo-EM samples, X. Wu for discussions on fitting crystallographic coordinates to cryo-EM maps, D. Bliss for assistance with preparing schematic illustrations, L. Earl, M. J. Borgnia and J. L. S. Milne for discussions, and S. Fellini, S. Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH.

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Authors

Contributions

J.R.M., M.L.M. and S.S. were involved in all stages of design of experiments and interpretation of the results; J.K. and S.C. carried out protein purification; P.R., J.P. and J.R.M. carried out data collection; P.R., J.P., J.R.M., A.B. and S.S. established workflows for data collection and handling; J.R.M. carried out image processing and 3D structure determination; A.B. carried out tilt pair plot analysis; J.R.M. and M.L.M. carried out detailed comparative analysis of cryo-EM structures with X-ray crystallographic studies of glutamate receptors; J.R.M., M.L.M. and S.S. integrated all of the data, analysis of the implications and mechanism, and wrote the manuscript.

Corresponding authors

Correspondence to Mark L. Mayer or Sriram Subramaniam.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Cryo-electron microscopic imaging of GluA2 with ZK200775.

ac, A series of representative images of GluA2 bound by the competitive antagonist ZK200775 (left panels), with corresponding power spectra and CTF estimates showing signal beyond 8 Å resolution (right panels, solid and dotted lines, respectively). Defocus values are 3.7, 2.7 and 3.0 μm for the three images, respectively. Scale bar, 100 nm.

Extended Data Figure 2 Antagonist-bound closed state GluA2 density map quality and resolution.

a, b, GluA2em antagonist-bound closed state density map with coordinates for ATD dimers, LBD dimers, and the transmembrane domain tetramer independently fit to the map. All coordinates were derived from PDB 3KG2. In panel b the density map is shown at a higher contour than a to highlight the closeness of fit between X-ray coordinates and the density map in the ATD and LBD layers. The density for the ATD–LBD linker region is weaker than that in the rest of the map and is therefore not visible at this threshold. The black bounding box in b identifies the M3-helix bundle crossing visible in the density map. c, Visualization of density map to highlight variation in resolution across different regions of the map. The estimated resolution value is colour-coded using the scale shown at the bottom edge of the panel. d, Expanded versions of selected regions of map. Roman numerals identify helices 6 and 8, loop 1, and the pre-M1 and M1 helices as indicated in panels a and b. e, A set of plots that include gold-standard FSC plot (black line) for the GluA2em antagonist-bound closed state density map showing a resolution of 10.4 Å at an FSC value of 0.143, and a plot (red line) of the FSC between the experimentally obtained cryo-EM density map and a map computed from the fitted coordinates, which displays a resolution of 10.6 Å at an FSC value of 0.5, consistent with the gold-standard FSC curve. f, Validation of density map using tilt-pair parameter plot. The spread in orientational assignments around the known goniometer settings is within 25° for >80% of the selected particle pairs, with clear clustering observed at the expected location, centred at a distance of 10° from the origin.

Extended Data Figure 3 Assessment of correspondence between GluA2em and GluA2cryst.

a, b, Density map of antagonist-bound closed state GluA2em with rigid body fits of GluA2cryst (PDB 3KG2) reveals separation between the ATD and LBD layers in GluA2em that is absent in GluA2cryst due to deletion of six residues in the ATD–LBD linker. In a, GluA2cryst fitting was performed using only ATD tetramer coordinates, which reveals a good fit of the ATD layer, but at the expense of the closeness of fit of the LBD assembly. Conversely, in b fitting was performed using only LBD tetramer coordinates, which reveals a good fit of the LBD layer, but at the expense of the closeness of fit of the ATD assembly. The black boxes highlight examples of regions where the mismatches are clearly evident.

Extended Data Figure 4 Open state GluA2 density map quality and resolution.

a, b, Density map of glutamate-bound GluA2em in the open state with coordinates for ATD dimers (PDB 3KG2) and glutamate-bound LBD dimers (PDB 1FTJ) fit separately into the map. In panel b the density map is shown at a higher contour than a to highlight closeness of fit between X-ray domain coordinates and the density map. c, Secondary structural features from ATD chains B/D of the density map corresponding to regions marked in panel b. Roman numerals identify helices 5, 6, 7 and the ATD lower domain β-sheet. d, Gold-standard FSC plot (black line) for the GluA2em open state density map showing a map resolution of 12.8 Å at an FSC value of 0.143, and a plot (red line) of the FSC between the experimentally obtained cryo-EM density map and a map computed from the fitted coordinates, which displays a resolution of 12.7 Å at an FSC value of 0.5, consistent with the gold-standard FSC curve.

Extended Data Figure 5 Desensitized state GluA2 density map classes and resolutions.

a, Three quisqualate-bound GluA2em desensitized state classes resolved through 3D classification. The maps are the same as those presented in Fig. 3b, but without segmentation to identify the ATD and LBD regions. b, Gold-standard FSC plots for the GluA2em desensitized state density maps showing resolutions of 21.4 Å, 25.9 Å and 22.9 Å for classes 1, 2 and 3, respectively at an FSC value of 0.143.

Extended Data Figure 6 Restored open state density map for the GluA2 quisqualate-LY451646 complex.

a, Density map for the GluA2em open state obtained by addition of the allosteric modulator LY451646 to a suspension of quisqualate-bound, desensitized GluA2. The purpose of the experiment was to test whether structural changes resulting from quisqualate binding to generate the desensitized state could be reversed by addition of an excess of the allosteric modulator LY451646, used to stabilize the open state. The map display shown on the left is colour-coded to highlight variation in resolution across different regions of the map. b, Density map for the glutamate-bound open state obtained by addition of LY451646 30 min before agonist, as shown in Fig. 2. The map display shown on the left is colour-coded as in a to highlight variation in resolution across different regions of the map. Comparison of the two maps and the fits of ATD and LBD dimers shows that they are essentially identical, establishing that the conformational changes that occur with desensitization are reversible and can be modulated by allosteric modulators.

Extended Data Figure 7 Cryo-electron microscopic imaging of GluK2 with 2S,4R-4-methylglutamate and 2D classes.

a, b, Representative cryo-EM image of GluK2 bound by the agonist 2S,4R-4-methylglutamate (a), with the corresponding image power spectrum and CTF estimate showing signal beyond 8 Å resolution (b, solid and dotted lines, respectively). The defocus value of the image is 3.7 μm. Scale bar is 100 nm. c, Two-dimensional classes of desensitized GluK2 particles subjected to single-particle analysis. d, Gold-standard FSC plot (black line) for the GluK2 desensitized state density map showing a map resolution of 7.6 Å at an FSC value of 0.143. A plot (red line) of the FSC between the experimentally obtained cryo-EM density map and a map computed from the fitted coordinates displays a resolution of 7.7 Å at an FSC value of 0.5, consistent with the gold-standard FSC curve.

Extended Data Figure 8 Resolution of the desensitized GluK2 density map.

a, GluK2 desensitized state map shown at increasing contour levels from left to right, to better highlight selected secondary structural features. b, Validation of density map using tilt-pair parameter plot. The spread in orientational assignments around the known goniometer settings is within 25° for >60% of the selected particle pairs, with clear clustering observed at the expected location, centred at a distance of 10° from the origin. c, Distal (left) and proximal (right) ATD subunits fit with the corresponding X-ray coordinates (PDB 3H6G). d, Proximal (left) and distal (right) LBD subunits fit with the corresponding X-ray coordinates for glutamate-bound GluK2 LBD monomers (PDB 3G3F). The close similarity in density maps for the individual ATD and LBD monomers of distal and proximal domains that are unrelated by computationally imposed C2 symmetry shows that the LBD monomers move largely as rigid bodies and that the structural changes that occur with desensitization can be described adequately by rigid body movements of the ATD and LBD monomers.

Extended Data Figure 9 Comparison between single particle and tomographic reconstructions of desensitized GluK2.

a, b, Single-particle reconstruction of desensitized GluK2 (a) shown adjacent to the previously reported structure from subvolume averaging (b). The overall envelope of the two structures is the same, but there is a difference in their lengths. This difference can be accounted for by considering the effect of the missing wedge on the tomographic structure in b. cf, When the two receptor structures are viewed looking down the receptor axis from the extracellular side, ATD layers (c, d) and LBD layers (e, f) can be seen to have the same arrangement. The ATD layer from the single-particle structure indicates contact within the ATD tetramer interface (c), and also between LBD monomeric domains (e). As a consequence of the missing wedge in the subtomogram average structure, lateral connectivity in the ATD layer (d) and LBD layer (f) is less evident.

Extended Data Table 1 Data collection and structural analysis

Supplementary information

Conformational changes that occur with transition from resting to open state in GluA2

Conformational changes that occur upon transition of GluA2 in the antagonist-bound closed state to the glutamate-bound open state. Crystal structure coordinates are colored with protomers A, B, C, and D in green, red, yellow and blue, respectively. α—helix G of each LBD is colored in orange. The trajectory was computed using the morph utility in PyMol by interpolation from the initial and final states derived from fitting atomic coordinates to cryo-EM density maps using UCSF Chimera. (MOV 12373 kb)

Conformational changes that occur with transition from open to desensitized state in GluK2

Conformational changes that occur in the LBD tetramer assembly upon transition of GluK2 in the glutamate-bound active state to the glutamate-bound desensitized state. Crystal structure coordinates are colored with protomers A, B, C, and D in green, red, yellow and blue, respectively. α—helix G of each LBD is colored in orange. The trajectory was computed using the morph utility in PyMol by interpolation from the initial and final states derived from fitting atomic coordinates to cryo-EM density maps using UCSF Chimera. (MOV 11503 kb)

Comparison of activation models

Comparison of structural changes in the GluA2 LBD tetramer assembly for the GluA2em active state structure, and models created in prior studies. Crystal structure coordinates are colored with protomers A, B, C, and D in green, red, yellow and blue, respectively. For GluA2em and models 1-3 trajectories from the antagonist-bound closed state to the glutamate bound active state were computed using the morph utility in PyMol. Model 1 was created by superimposing two copies of GluA2 LBD glutamate complex dimers (PDB ID: 1FTJ) on GluA2cryst, using domain 1 coordinates (RMSD 0.31 Å); note that different from the GluA2em active state, the upper lobes of the LBD do not move. Model 2 was created by generating a GluA2 LBD tetramer assembly with crystallographic symmetry operations starting from PDB ID: 1FTJ; note that the upper lobes move closer together, and that in the active state the assembly assumes a flat structure in which the dimers are arranged as parallel arrays. Model 3 is the activation intermediate tetramer assembly generated by crystallographic symmetry operations from PDB ID 4L17, for which the B and D subunit DNQX-bound protomers were replaced by glutamate bound protomers (PDB ID 1FTJ); note that similar to model 2, the upper lobes move closer together, and that in the active state, the assembly assumes a flat structure in which the dimers are arranged as parallel arrays. (MOV 12305 kb)

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Meyerson, J., Kumar, J., Chittori, S. et al. Structural mechanism of glutamate receptor activation and desensitization. Nature 514, 328–334 (2014). https://doi.org/10.1038/nature13603

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