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Structural basis of ketamine action on human NMDA receptors

Nature volume 596, pages 301–305 (2021)Cite this article

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An Author Correction to this article was published on 14 October 2021

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Abstract

Ketamine is a non-competitive channel blocker of N-methyl-d-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture containing equal parts of (R)- and (S)-ketamine, with the (S)-enantiomer having greater affinity for the NMDA receptor4. Here we describe the cryo-electron microscope structures of human GluN1–GluN2A and GluN1–GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids—leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1—were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.

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Fig. 1: S-ketamine-bound cryo-EM structures of human GluN1–GluN2A and GluN1–GluN2B NMDA receptors.
Fig. 2: MD simulation of the S-ketamine-bound TMD of the GluN1–GluN2A receptor.
Fig. 3: Mechanism by which ketamine inhibits GluN1–GluN2A and GluN1–GluN2B NMDA receptors.

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Data availability

The cryo-EM maps and structure coordinates for GluN1–GluN2A and GluN1–GluN2B receptors have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-31308 and EMD-31309, and in the Protein Data Bank under accession numbers 7EU7 and 7EU8, respectively. The structures of S-ketamine and R-ketamine are accessible from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) under compound CIDs 182137 and 644025, respectively. The human missense mutation c.1925T>G (L642R) in GRIN2A was retrieved from the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) under variation ID 985631. Additional data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank B. Zhu, X. Li, C. Liu, F. Meng and Z. Guo for their assistance with cryo-EM data collection; H. Wang, J. Zhang and Y. Gu for assistance with experiments; Y. Sun for advice on human NMDA receptor variants; and M. Poo and E. Xu for proofreading. Financial support is gratefully acknowledged from the National Natural Science Foundation of China (31771115), the National Key R&D Program of China (2017YFA0505700), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB32020000), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX05) and the Thousand Young Talents Program to S.Z.; and the National Natural Science Foundation of China (81625022, 91853205, 81821005) and the Shanghai Municipal Health Commission in China (18431907100 and 19XD1404700) to C.L.

Author information

Author notes

  1. These authors contributed equally: Youyi Zhang, Fei Ye, Tongtong Zhang

Authors and Affiliations

  1. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Youyi Zhang, Tongtong Zhang, Shiyun Lv & Shujia Zhu

  2. University of Chinese Academy of Sciences, Beijing, China

    Youyi Zhang, Tongtong Zhang, Shiyun Lv, Liping Zhou, Cheng Luo & Shujia Zhu

  3. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China

    Fei Ye

  4. Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Liping Zhou, Daohai Du, Fei Guo & Cheng Luo

  5. Criminal Investigation Technology Department, The Third Research Institute of Ministry of Public Security, Shanghai, China

    He Lin

  6. Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China

    Shujia Zhu

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Contributions

Y.Z. and T.Z. purified and froze the protein, collected and analysed the cryo-EM data, built the atomic model and conducted electrophysiology on GluN1–GluN2A and GluN1–GluN2B receptors, respectively; F.Y., L.Z., and C.L. carried out the docking and MD simulation; D.D. assisted with binding assays; S.L. and F.G. participated in the data analysis; H.L. provided ketamine compounds; Y.Z., F.Y., T.Z. and S.Z wrote the manuscript with inputs from all the authors. S.Z. conceived the project and supervised the research.

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Correspondence to Cheng Luo or Shujia Zhu.

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Extended data figures and tables

Extended Data Fig. 1 Expression profile and functional validation of human GluN1–GluN2A and GluN1–GluN2B NMDA receptors.

a, Schematic representation of human GluN1EM (grey), GluN2AEM (green) and GluN2BEM (blue) CTD-truncated constructs. b, Representative fluorescence SEC and Coomassie blue gel staining of the purified GluN1–GluN2AEM (left) and GluN1–GluN2BEM receptors (right). Experiments were performed three times independently with similar results. c, d, Representative recording traces (left) and the fitted DRCs (right; mean ± s.d.) for (R,S)-ketamine inhibition on wild-type GluN1–GluN2A and GluN1–GluN2AEM (c), and wild-type GluN1–GluN2B and GluN1–GluN2BEM (d) receptors activated with 100 μM coagonists. Ketamine IC50 values, Hill slopes and numbers are listed in Extended Data Table 3.

Extended Data Fig. 2 Overview of cryo-EM image processing and 3D reconstruction of GluN1–GluN2A and GluN1–GluN2B NMDA receptors.

a, Flowchart of the image processing and 3D reconstruction of human GluN1–GluN2A receptors in complex with S-ketamine, glycine and glutamate. Typical single particles are circled in red from raw micrographs. The 2D class average images show characteristic 2D views in various orientations. The 3D classes with similar conformations were selected and combined through several rounds of 3D classification for final refinement. b, Fourier shell correlation (FSC) curve for the resolution estimation. c, Side view of the cryo-EM density map of GluN1–GluN2A receptor coloured by local resolution estimated by Relion 3.1. d, Pipelines for single-particle analysis and reconstruction of human GluN1–GluN2B receptor in complex with S-ketamine, glycine and glutamate. Same workflow as in a. e, FSC curve for the resolution estimation. f, Side view of the cryo-EM density map of GluN1–GluN2B receptor coloured by local resolution estimated by Relion 3.1.

Extended Data Fig. 3 Representative local densities in GluN1–GluN2A cryo-EM map with fitted atomic model.

a, b, Zoomed-in views of the GluN1-LBD cleft with EM density for glycine (a), and the GluN2A-LBD cleft with glutamate (b). Key binding residues are shown as sticks. c, d, Local densities in extracellular domains of the GluN1 (a) and GluN2A (b) subunits. EM densities are shown as light grey mesh, while the side chains and N-glycosylation sites of residues are represented as sticks.

Extended Data Fig. 4 Functional validation of the ketamine-binding pocket of NMDA receptors.

a, Representative I–V curves for Mg2+ blockage of wild-type GluN1–GluN2A receptors or receptors incorporating a substitution (A, N or V) at GluN2A-L642, recorded in the presence of 100 μM MgCl2. b, c, Plot of 3 μM ketamine inhibition level for wild-type (open circle) and mutant (filled circles) amino acid volume (I, V, A or G) at position GluN2B-L643 or GluN2D-L667, shown with a linear regression. R2 values equal to 0.72 for GluN1–GluN2B and 0.95 for GluN1–GluN2D receptors. d, e, (R,S)-Ketamine DRCs for the GluN1–GluN2A and GluN1–GluN2B wild-type or mutant receptors incorporating a substitution (A, L or T) at GluN1-V644. All IC50 values, Hill slopes and numbers of oocytes are listed in Extended Data Table 3. f, Schematic representation of the S-ketamine binding site on GluN1–GluN2B receptors analysed by Ligplot+.

Extended Data Fig. 5 Molecular basis of S- and R-ketamine-induced inhibition of GluN1–GluN2A receptors.

a, Chemical structures of left-handed S-ketamine and right-handed R-ketamine. b, r.m.s.d. trajectories for each chain (excluding M1–M2 loops) and R-ketamine were calculated on Cα atoms based on the initial structure within the whole simulation time of 500 ns. c, Left, R-ketamine poses obtained in MD simulation along the whole simulation time. Right, schematic diagram of R-ketamine and TMD interactions at 500 ns snapshot extracted from MD simulation. Residues involved in the hydrophobic interactions are shown as starbursts. d, Inhibition by 2 μM S-ketamine of NMDA receptor activity induced by saturating agonists in wild-type GluN1–GluN2A (0.606 ± 0.018, n = 9 oocytes), GluN1(N616A)–GluN2A (0.020 ± 0.004, n = 3), GluN1(N616Q)–GluN2A (0.027 ± 0.006, n = 3), GluN1–GluN2A(L642A) (0.041 ± 0.012, n = 3), GluN1–GluN2A(L642V) (0.152 ± 0.007, n = 3), GluN1–GluN2A(L642N) (0.020 ± 0.001, n = 3), GluN1(V644A)–GluN2A (0.333 ± 0.038, n = 3), GluN1(V644L)–GluN2A (0.455 ± 0.012, n = 3), GluN1(V644T)–GluN2A (0.602 ± 0.020, n = 3), GluN1(T648V)–GluN2A (0.621 ± 0.015, n = 3), GluN1–GluN2A(T646V) (0.532 ± 0.024, n = 4) and GluN1–GluN2A(N615A) (0.597 ± 0.008, n = 3) receptors. e, Inhibition by 2 μM R-ketamine of wild-type GluN1–GluN2A (0.404 ± 0.017, n = 9), GluN1(N616A)–GluN2A (0.008 ± 0.001, n = 3), GluN1(N616Q)–GluN2A (0.049 ± 0.008, n = 3), GluN1–GluN2A(L642A) (0.014 ± 0.001, n = 3), GluN1–GluN2A(L642V) (0.065 ± 0.009, n = 3), GluN1–GluN2A(L642N) (0.019 ± 0.001, n = 3), GluN1(T648V)–GluN2A (0.330 ± 0.021, n = 3), GluN1–GluN2A(T646V) (0.423 ± 0.021, n = 4) and GluN1–GluN2A(N615A) (0.344 ± 0.01, n = 3) receptors. f, Superposition of the 500 ns snapshots extracted from MD simulation of S-ketamine (pink) and R-ketamine (cyan) systems, respectively. g, Inhibition by 2 μM R- and S-ketamine of GluN1–GluN2A(N614A) (0.138 ± 0.009, 0.509 ± 0.014, n = 3) and GluN1–GluN2A(N614Q) (0.140 ± 0.006, 0.633 ± 0.014, n = 3) receptors. In d, e, g, all data shown are mean ± s.e.m.; P values are determined by one-way ANOVA with Dunnett’s multiple comparison test (****P < 0.0001). Each data point represents the result of one oocyte. h, R-ketamine (left) and S-ketamine (right) DRCs (mean ± s.d.) for wild-type GluN1–GluN2A (IC50: 2.39 ± 0.45 μM, n = 4 oocytes; 0.60 ± 0.03 μM, n = 3), GluN1–GluN2A(N614A) (13.66 ± 2.49 μM, n = 4; 1.22 ± 0.44 μM, n = 4) and GluN1–GluN2A(N614Q) (39.94 ± 6.72 μM, n = 4; 1.41 ± 0.38 μM, n = 4) receptors.

Extended Data Fig. 6 Sequence alignment and structural comparison of TMD in ionotropic GluRs.

a, Sequence alignment of TM2–TM3 segments in human GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluA2 and GluK2, Xenopus GluN1, GluN2B and rat GluA2 subunits. The critical residues involved in ketamine binding are highlighted in yellow, and their homologous sites in ionotropic GluRs are marked in rectangles. b, Superposition of the TM2 and TM3 segments between the S-ketamine (in brick red)-bound GluN1–GluN2BEM receptor and the MK-801 (in red)-bound GluN1–GluN2B(ΔNTD) receptor (PDB code: 5UN1)20. c, MK-801-bound TMD of the triheteromeric GluN1–GluN2A–GluN2B NMDA receptor, viewed parallel to the membrane (PDB code: 5UOW)25. MK-801 binding residues were analysed by LigPlot+ (right). d, e, Superposition of the TM2 and TM3 segments between the S-ketamine bound GluN1–GluN2AEM receptor and GluA2 AMPA receptor (PDB code: 5VOT)41 (d) or the GluK2 kainate receptor (PDB code: 5KUF)42 (e). All superpositions are based on the α-carbon atoms of the conserved SYTANL region.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Full size table
Extended Data Table 2 Per-residue decomposition of relative binding energy for residues within 10 Å of S-ketamine
Full size table
Extended Data Table 3 Summary of potency of (R,S)-ketamine on human GluN1–GluN2A and GluN1–GluN2B receptors
Full size table
Extended Data Table 4 Per-residue decomposition of relative binding energy for residues within 10 Å of R-ketamine
Full size table

Supplementary information

Supplementary Figure 1

Uncropped gels presented in the Extended Data Fig. 1.

Reporting Summary

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Video 1

Motions of GluN1-GluN2A TMD in complex with S-ketamine (brick-red) and R-ketamine (blue) during the 500 ns MD simulation. The TMD of GluN1 and GluN2A subunits are shown in grey and green, respectively.

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Zhang, Y., Ye, F., Zhang, T. et al. Structural basis of ketamine action on human NMDA receptors. Nature 596, 301–305 (2021). https://doi.org/10.1038/s41586-021-03769-9

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