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X-ray structures and mechanism of the human serotonin transporter

Abstract

The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.

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Figure 1: Function and architecture of the human serotonin transporter.
Figure 2: Antidepressant binding and recognition.
Figure 3: Allosteric site.
Figure 4: Structural features of the allosteric site.
Figure 5: Comparison of serotonin and dopamine transporters.
Figure 6: Allosteric modulation of inhibitor binding.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factors have been deposited in the Protein Data Bank (PDB) under the following accession codes: ts3 paroxetine (5I6X), ts2 paroxetine (5I6Z), ts3 (S)-citalopram (5I71), ts3 (S)-citalopram (soaked) (5I73), ts3 Br-citalopram (5I74), ts3 Br-citalopram (soaked) (5I75), and 8B6 Fab (5I66).

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Acknowledgements

We thank D. Cawley for generating monoclonal antibodies and Lundbeck for Br-citalopram. We thank A. Penmatsa and K. Wang for assistance with initial crystal screening, K. Dürr and W. Lü for help with Fab crystallization and structure refinement, respectively, L. Vaskalis for assistance with figures, H. Owen for help with manuscript preparation and other Gouaux laboratory members for discussions. We acknowledge the staff of the Berkeley Center for Structural Biology at the Advanced Light Source and the Northeastern Collaborative Access Team at the Advanced Photon Source for assistance with data collection. J.A.C. has support from a Banting postdoctoral fellowship from the Canadian Institutes of Health Research. We are particularly grateful to Bernie and Jennifer LaCroute for their generous support, as well as for funding from the National Institutes of Health (NIH) (5R37MH070039). E.G. is an Investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

Authors

Contributions

J.A.C., E.M.G. and E.G. designed the project. E.M.G. and J.A.C. developed thermostable constructs for crystallization. J.A.C. performed protein purification, crystallography and biochemical analysis. J.A.C., E.M.G. and E.G. wrote the manuscript.

Corresponding author

Correspondence to Eric Gouaux.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Construct design and secondary structure.

Thrombin digestion sites were introduced within the N- and C-terminal regions before Gln76 and after Thr618. Mutations which were introduced to increase thermostability (Tyr110Ala, Ile291Ala and Thr439Ser) are indicated (red star). Surface exposed cysteine residues were mutated to alanine (Cys554 and Cys580) and indicated by a blue star. Residues that have no electron density are boxed in green. Secondary structure was analysed using DSSP (http://swift.cmbi.ru.nl/gv/dssp/) and displayed using ENDScript (http://endscript.ibcp.fr/). Secondary structure elements are shown using the following symbols: α-helix (α), β-strand (β), π-helix (π), 310 helix (η), β-turn (TT letters), α-turn (TTT letters). Locations of carbohydrate (red, ″) and disulfide bonding cysteine (green digits) residues are also shown. A–C in italic means the residue has a crystallographic contact with a residue in chain A–C. The ‘#’ symbol identifies a contact between two residues along the crystallographic two-fold axis of symmetry. Contacts between transporter residues and small molecules in the range of 3.2–5.0 Å are also indicated (black, ″). Hydropathy is calculated according to Kyte and Doolittle59 and shown with pink as hydrophobic (H > 1.5), cyan as hydrophilic (H < 1.5), and grey as intermediate. The secondary structure of the dopamine transporter (4M48) is shown for comparison.

Extended Data Figure 2 Comparison of the ts3 and ts2 structures, crystal packing and antibody structure.

a, Superposition of the ts2 (blue) and ts3 (grey) transporters, each in complex with paroxetine using all atoms (Extended Data Table 3). Paroxetine (pink sticks) and thermostabilizing mutations (yellow spheres). b, Position of amino acid changes due to single nucleotide polymorphisms and mutants associated with psychiatric disorders (yellow). Paroxetine is shown in pink. c, SERT is shown in green, Fab heavy chain (orange), light chain (blue). SERT molecules pack into the crystal lattice with SERT–SERT interface occurring along the kink of TM12 helices related by the crystallographic two-fold axis (blue box). d, Rotation by 90° reveals further lattice contacts. Red box shows interface between Fab, EL2 and EL4. We predict that this interface contains the high-affinity interaction of the Fab with EL2 and EL4. Also shown is an EL2–EL2 interaction between symmetry related molecules as well as a Fab–EL2 interface in the asymmetric unit. Purple box shows interface between Fab variable domains. Black box shows crystal contact between the C-terminal helix and the Fab constant domain. e, The binding site of the 8B6 Fab is made up of interactions of residues from EL2 and EL4 (sticks). f, Comparison of the high resolution Fab structure (grey) with SERT-bound Fab (Extended Data Table 3). The largest structural changes occur in the complementary determining regions (CDRs).

Extended Data Figure 3 Comparison of ligand binding in SERT and in DAT.

a, Comparison of SERT bound to paroxetine with dDAT (4M48) bound to nortriptyline (yellow); superposition based on TM1–TM12. SERT is shown in blue and DAT in grey. b, Alignment of paroxetine (blue) and (S)-citalopram (pink) structures using all atoms in superposition (Extended Data Table 3). Residues interacting with the antidepressant molecules are shown as sticks. Paroxetine (pink) and (S)-citalopram (green) are shown as sticks. c, Insertion of benzodioxol and fluorophenyl groups of paroxetine and (S)-citalopram into a cavity in subsite B made up of Leu443, Ala169, Ala173 and Ser439. Note that Ser439 is equivalent to Thr439 in wild-type SERT. Equivalent residues in dDAT are shown in grey.

Extended Data Figure 4 Ion-binding sites.

a, Overall view of the Na1 and Cl ion binding sites in the paroxetine bound transporter. Na+ (salmon) and Cl (green) are shown as spheres. Paroxetine is shown as pink sticks. b, Overall view of the (S)-citalopram bound transporter showing the Na2 binding site; (S)-citalopram (green sticks). c, Residues coordinating Na1 and Cl. Ion Fo − Fc omit densities are shown at 2σ and 3σ for Na1 and Cl. d, Residues coordinating Na2. Fo − Fc omit density is shown at 4σ. A water molecule is shown as a yellow sphere. Coordination distances are given in Extended Data Table 4.

Extended Data Figure 5 Extracellular and intracellular gates and the allosteric site of paroxetine and partially occupied (S)-citalopram.

a, The extracellular gate of the SERT–(S)-citalopram complex is shown, with (S)-citalopram bound to the central site. The width of the gate is depicted by the distances between Tyr176 and Phe335 (10.3 Å, CD1–CE2), Asp98 and Tyr176 (4.0 Å, OD2–OH), Glu494 and Arg104 (4.9 Å, OE1–NH1) dDAT (grey) is shown for comparison. b, Comparison of the intracellular gate of SERT (pink) versus DAT (4M48, grey). Superpositions were made by alignment of TM1–TM12 of SERT with dDAT. c, The allosteric site containing fully occupied (S)-citalopram (pink) was superposed with the partially occupied structure (olive). The Fo − Fc omit density (blue mesh) of the partially occupied structure is shown at 2σ. (S)-citalopram is shown in green sticks. A 12-carbon chain (magenta) was modelled into this density but could instead represent a partially occupied (S)-citalopram. The structure with partial (S)-citalopram occupancy at the allosteric site was derived from crystals grown in the presence of 10 μM ligand. Crystals with a higher occupancy at the allosteric site were soaked in a solution containing 5 mM (S)-citalopram before crystal cryo protection. d, The paroxetine-bound transporter contains a maltose detergent headgroup (orange) bound to the allosteric site. Fo − Fc maltose omit density at 3σ.

Extended Data Figure 6 Cholesteryl hemisuccinate and tetradecane binding sites.

a, Overall view of the (S)-citalopram-bound structure showing CHS (red box) and tetradecane (C14, blue box). b, Zoomed view of the CHS binding site. Residues near CHS are shown as sticks. The Fo − Fc omit density map is shown at 3σ. c, Binding of tetradecane. The Fo − Fc omit density map is contoured at 4σ. d, Tetradecane was modelled on a two-fold axis of symmetry with partial occupancy as a single molecule. On the basis of the density, it is unclear if this molecule represents the alkyl chain of a lipid, detergent, or a molecule of PEG.

Extended Data Table 1 Data collection and refinement statistics
Extended Data Table 2 Anomalous data collection and refinement statistics
Extended Data Table 3 Superpositions of DAT, LeuT, ts2 SERT and ts3 (S)-citalopram conformational states versus ts3 SERT (paroxetine) and comparison of high-resolution Fab versus SERT-bound Fab (paroxetine)
Extended Data Table 4 Ion-binding sites and coordination distances

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Coleman, J., Green, E. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016). https://doi.org/10.1038/nature17629

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