Abstract
Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter1,2 that activates the largest subtype family of G-protein-coupled receptors3. Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders4. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor–G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein–5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules—particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.
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Data availability
Density maps and structure coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and the PDB with accession codes EMD-30971 and 7E2X for the apo–5-HT1A–Gi complex; EMD-30972 and 7E2Y for the 5-HT–5-HT1A–Gi complex; EMD-30973 and 7E2Z for the aripiprazole–5-HT1A–Gi complex; EMD-30974 and 7E32 for the 5-HT–5-HT1D–Gi complex; and EMD-30975 and 7E33 for the 5-HT–5-HT1E–Gi complex.
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Acknowledgements
The cryo-EM data were collected at the Center of Cryo-Electron Microscopy, Zhejiang University, and at the Center of Cryo-Electron Microscopy, Shanghai Institute of Materia Medica. This work was partially supported by the National Key R&D Programs of China (2018YFA0507002); the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02); the CAS Strategic Priority Research Program (XDB37030103) to H.E.X.; the National Key Basic Research Program of China (2019YFA0508800); the National Natural Science Foundation of China (81922071); the Zhejiang Province Natural Science Fund for Excellent Young Scholars (LR19H310001); Fundamental Research Funds for the Central Universities (2019XZZX001-01-06) to Y.Z.; the National Natural Science Foundation (31770796) and National Science and Technology Major Project (2018ZX09711002-002-002) to Y.J.; the Fund of Youth Innovation Promotion Association (2018319 Y8G7011009) to X.C.; the Science and Technology Commission of Shanghai Municipal (20431900100) and Jack Ma Foundation (2020-CMKYGG-05) to H.J.; the EU Horizon 2020, Innovative Training Network SAFER (765657) to I.A.S.; the Lundbeck Foundation (R163-2013-16327) and Novo Nordisk Foundation (NNF18OC0031226) to D.E.G. and K.H.; and a Wellcome Trust Investigator Award (104633/Z/14/Z) to C.V.R. and H.-Y.Y.
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Contributions
P.X. and S.H. designed the expression constructs, purified the complexes, prepared samples for negative stain and for the collection of data relating to the structures, and prepared the figures and manuscript draft. P.X., H.Z., C.M. and D.-D.S. evaluated the specimens by negative-stain electron microscopy, screened cryo-EM conditions, prepared cryo-EM grids, collected cryo-EM images, processed cryo-EM data and participated in the preparation of supplementary figures. X.E.Z., P.X. and H.Z. built the models and refined the structures. I.A.S. and K.H. conducted analyses of ligand–receptor structure–activity relationships and contributed to writing. K.H. performed data curation of mutagenesis data. B.S. and D.E.G. were responsible for the funding and supervision of I.A.S. and K.H., and participated in writing. X.C. and H.J. were responsible for molecular dynamics simulation studies, ligand-docking studies and writing of methods. K.M. supervised X.E.Z. and participated in writing. H.-Y.Y. and C.V.R. analysed lipid composition and edited the manuscript. Y.J. participated in the supervision of P.X. and S.H., fund acquisition and paper editing. Y.Z. supervised the cryo-EM data collection and data analysis, and participated in writing. H.E.X. conceived and supervised the project, analysed the structures and wrote the manuscript with input from all authors.
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Extended data figures and tables
Extended Data Fig. 1 Sample preparation and cryo-EM of the 5-HT1A–Gi complexes.
a, Analytical size-exclusion chromatography of the purified complex. b, SDS–PAGE and Coomassie blue stain of the purified complex. Experiments were repeated three times with similar results. c, Representative cryo-EM image (scale bar, 30 nm) from 4,179 movies and 2D averages (scale bar, 5 nm) of the 5-HT–5-HT1A–Gi complex. Experiments were repeated three times with similar results. d–f, Flow chart of cryo-EM data analysis and local resolution for the densities of the apo- (d), 5-HT-bound (e) and aripiprazole-bound (f) 5-HT1A–Gi complexes. g, ‘Gold-standard’ FSC curves. h, Local resolution for the density of water molecules (W1–W4) in the ligand-binding pocket of the apo-5-HT1A–Gi structure.
Extended Data Fig. 2 Sample preparation and cryo-EM of the 5-HT1D–Gi–scFv16 and 5-HT1E–Gi–scFv16 complexes.
a, b, Analytical size-exclusion chromatography and SDS–PAGE and Coomassie blue stain of the purified 5-HT1D–Gi–scFv16 complex (a) and the 5-HT1E–Gi–scFv16 complex (b). Experiments were repeated three times with similar results. c, Representative cryo-EM image (scale bar, 30 nm) from 4,375 movies and 2D averages (scale bar, 5 nm) of the 5-HT1D–Gi–scFv16 complex. d, Representative cryo-EM image (scale bar, 30 nm) from 5,249 movies and 2D averages (scale bar, 5 nm) of the 5-HT1E–Gi–scFv16 complex. e, f, Flow chart of cryo-EM data analysis, local resolution for the density and the ‘gold-standard’ FSC curves of the 5-HT1D–Gi–scFv16 complex (e) and the 5-HT1E–Gi–scFv16 complex (f).
Extended Data Fig. 3 Lipid regulation in 5-HT1A.
a–c, The cryo-EM map of the apo–5-HT1A–Gi complex and the surrounding lipids are shown with different thresholds of 0.025 (a), 0.03 (b) and 0.04 (c). d, Interactions of PtdIns4P (here labelled as PI4P) at the 5-HT1A–Gi interface. e, Interaction of the PtdIns4P head group with the TM6, TM and Gαi pocket. Hydrogen bonds are shown with dashed lines. f, Comparison of the density fitting for PtdIns4P, phosphatidylinositol and PtdIns(4,5)P2 (here labelled as PIP2). The area of density that is not well fit is circled by a dashed line. g, 5-HT1A-mediated Gi activity is regulated by phosphatidylinositol, PtdIns4P and PtdIns(4,5)P2, with the greatest degree of regulation by PtdIns4P. GTPase-Glo assay was performed in LNMG buffer. Lower levels of residual GTP indicate higher levels of G-protein activity upon receptor-mediated GDP exchange for GTP and GTP hydrolysis. Data are mean ± s.d. of three independent experiments performed in technical triplicate. **P < 0.01, ***P < 0.001, ****P < 0.0001 (two-tailed paired t-test).
Extended Data Fig. 4 Cholesterol regulation in 5-HT1A.
a, The model of the 5-HT1A–Gi complex shows multiple cholesterol molecules bound to the surface of 5-HT1A. The 5-HT1A–Gi complex is shown as surface and lipids are shown as sticks. b, Interactions of cholesterol molecule 1 (#1) with TM1 and TM7 of 5-HT1A. c, Interactions of cholesterol molecules 2 and 3 with 5-HT1A. d, The effect of cholesterol on the 5-HT potency to activate 5-HT1A. The effects of mutations at the binding residues of cholesterol molecule 1 on 5-HT-mediated activation of 5-HT1A (pEC50; the negative logarithm of EC50) were detected by NanoBiT recruitment assays. Data are mean ± s.d. from at least three independent experiments performed in technical triplicate. *P < 0.05, **P < 0.01 (two-tailed paired t-test).
Extended Data Fig. 5 Basal activity and ligand-induced activation of 5-HT1A.
a, Detection of the ligand-reduced activity and constitutive activity of human 5-HT1A by NanoBiT G-protein-recruitment assay. Three ligands—the full agonist 5-HT, the neutral antagonist WAY-100635 and the inverse agonist methiothepin—were used. Data are mean ± s.e.m. of three independent experiments performed in technical triplicate. b, Water molecules are coordinated in the ligand-binding pocket of the apo-5-HT1A structure. The density is shown at a cut-off of 3σ. c–f, Activation of 5-HT1A by 5-HT and binding to apo-5-HT1A by water molecules. Toggle switch in the 5-HT-bound 5-HT1A structure (c) and the apo-5-HT1A structure (e). PIF motif in the 5-HT-bound 5-HT1A structure (d) and the apo-5-HT1A structure (f). The 5-HT-bound 5-HT1A structure is coloured in turquoise; the apo-5-HT1A is coloured in green; 5-HT is coloured in orange. Aligned structures of the inactive-state 5-HT1B (bound to the inverse agonist methiothepin) and the intermediate-state 5-HT1B (bound to the agonist ERG) are coloured in grey and light grey. Conformational changes of the toggle-switch residue Trp3586 48 and the residue Phe3546.44, which is part of a conserved PIF motif, are illustrated by arrows. g–i, The hydrogen-bonding network of the ligand-binding pocket observed in the molecular dynamics simulations. Side view (g) and top view (h) of a hydrogen-bonding network linking the key residues of the active apo-5-HT1A receptor. i, Top view of water molecules accommodated in the inactive apo-5-HT1A receptor. The structure of the apo-5-HT1A is coloured in light blue. A representative conformation from the active apo-5-HT1A simulations is coloured in light green. A representative conformation from the inactive apo-5-HT1A simulations is coloured in grey. The structured water molecules W1 and W2 of the apo-5-HT1A–Gi complex structure are shown as spheres. Putative hydrogen bonds are shown with dashed lines.
Extended Data Fig. 6 Ligand recognition in 5-HT1A, 5-HT1D and 5-HT1E.
a, d, g, j, Conformation of the ligand-binding pockets in 5-HT-bound 5-HT1A (a), 5-HT-bound 5-HT1D (d), BRL-54443-bound 5-HT1E (g) and aripiprazole-bound 5-HT1A (j). b, e, h, k, Diagram of ligand recognition for 5-HT in 5-HT1A (b), 5-HT in 5-HT1D (e), BRL-54443 in 5-HT1E (h), and aripiprazole in 5-HT1A (k). c, f, i, l, Ligand-binding pockets shown as surfaces. The orthosteric binding pocket is highlighted in orange.
Extended Data Fig. 7 Ligand-binding pocket mutagenesis data by NanoBiT Gi-protein-recruitment assay.
Data are mean ± s.e.m. from at least three independent experiments performed in technical triplicate. The EC50 ratio, EC50(mutant)/EC50(WT), represents the shift between the wild-type and mutant curves, and characterizes the effect of the mutations on receptor activation.
Extended Data Fig. 8 5-HT-binding pocket alignment and ligand affinity among 5-HT receptors.
a, Dendrogram and sequence alignment on the basis of residues that line the 5-HT-binding pocket (cut-off of 5 Å). Identical residues are marked in white, whereas non-conserved residues are coloured by their physicochemical properties. b, Binding affinities (pKi values) for selected ligands of the 5-HT receptors (https://pdsp.unc.edu/pdspweb/).
Extended Data Fig. 9 Selectivity of receptors of the 5-HT1 subfamily.
a, Fitted regression model versus experimental binding affinities of 5-HT, 5-MeOT, 5-CT and donitriptan for the 5-HT GPCRs. b–d, 5-HT- (b), 5-CT- (c) and donitriptan-(d) induced Gi activation assay using NanoBiT for wild-type 5-HT1A, 5-HT1D and 5-HT1E receptors. Data are mean ± s.e.m. from at least three independent experiments performed in technical triplicate. e, 5-CT-induced Gi activation assay using NanoBiT for 5-HT1E, and concentration–response curves for G-protein-recruitment signals. Data are mean ± s.e.m. from at least three independent experiments performed in technical triplicate. f, g, The different side chains at the transmembrane domain (f) and at ECL2 (g) that determine the recognition for donitriptan among 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1E. h, Docked pose of donitriptan in donitriptan-bound 5-HT1A (right), 5-HT1D (middle) and 5-HT1E (left).
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Xu, P., Huang, S., Zhang, H. et al. Structural insights into the lipid and ligand regulation of serotonin receptors. Nature 592, 469–473 (2021). https://doi.org/10.1038/s41586-021-03376-8
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DOI: https://doi.org/10.1038/s41586-021-03376-8
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