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.2021 Jun 3;12(1):3305.
doi: 10.1038/s41467-021-23519-9.

Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

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Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist

Bingfa Sun et al. Nat Commun..

Abstract

Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.

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Conflict of interest statement

S.L., Z.A.S., S.K., A.V., M.W., and T.C. are employees of UCB Pharma and may own company stock. B.S., D.F., M.L.C., I.F., T.S.K., and B.K.K. are employees of or consultants for ConfometRx. T.S.K. and B.K.K. cofounded ConfometRx.

Figures

Fig. 1
Fig. 1. Overall structure of D1R in complex with Gs and non-catechol agonist Compound 1.
a The structure of D1R and Gs are shown in cartoon, and ligand Compound 1 is shown in spheres. D1R: green; Compound 1: lime; Gαs: blue; Gβ: orange; Gγː purple; Nb35: light pink.b Superimposition of D1R-Gs structure with β2AR-Gs structure by receptor (gray for β2AR, cyan for Gαs, light orange for Gβ, violet for Gγ; PDB ID: 3SN6) shows a longer TM5-ICL3 helix in D1R, which interacts with the α4 helix and α4-αg loop of Gαs.c Differences in the relative orientation of the Gs trimer and receptor for D1R-Gs and β2AR-Gs structures following superimposition of the receptors.
Fig. 2
Fig. 2. The binding of non-catechol agonist Compound 1 to D1R.
a The chemical structure of Compound1.b Binding pocket of Compound1. Residues within the interaction distance of the ligand are shown in stick. Hydrogen bonds are depicted with dashed lines.c ECL2 of D1R adopts a unique bulged conformation to accommodate Compound1 (shown in stick). D1R structure is aligned with multiple aminergic receptor structures. All other bound ligands are shown in lines. D1R: green, Compound1: lime; β2AR, gray (PDB ID: 4LDO); D2R: orange (PDB ID: 6VMS); 5-HT2C, magenta (PDB ID: 6BQG); 5-HT1B, yellow (PDB ID: 4IAR); β1AR, purple (PDB ID: 2Y03); D4R, cyan (PDB ID: 5WIV); D3R, blue (PDB ID: 3PBL); 5-HT2B, dark green (PDB ID: 4IB4).d Surface representation of Compound1 binding pocket. Compound1 is shown in spheres, while the side chain of Leu190 on ECL2 of D1R is shown in stick.
Fig. 3
Fig. 3. Unique features of the D1R ligand binding pocket.
a Sequence alignment of aminergic receptors at ECL2, starting from the conserved cysteine, as well as 7.43 position (Ballesteros–Weinstein numbering). The residues at cysteine+2, cysteine+4 and 7.43 positions are highlighted, as they are unique in D1R/D5R.b The side chain orientations of the +2 residues (position indicated by dashed line) on ECL2, counting from the conserved disulfide bond forming cysteine residue. Compound1 and Ser188 (cysteine+2 residue), L190 (cysteine+4 residue) of D1R, as well as all disulfide bonds are shown in stick, while cysteine+2 residues on other aminergic receptors are shown in line. D1R: green, Compound1: lime; β2AR, gray (PDB ID: 4LDO); D2R: orange (PDB ID: 6VMS); 5-HT2C, magenta (PDB ID: 6BQG); 5-HT1B, yellow (PDB ID: 4IAR); b1AR, purple (PDB ID: 2Y03); D4R, cyan (PDB ID: 5WIV); D3R, blue (PDB ID: 3PBL); 5-HT2B, dark green (PDB ID: 4IB4).c Trp3217.43 is a unique feature in the D1R orthosteric site. D1R structure is aligned with 5-HT2B bound to ergotamine (dark green, PDB ID: 4IB4) and LSD (hot pink, PDB ID: 5TVN), and D2R bound to bromocriptine (orange, PDB ID: 6VMS). The Van der Waals radius of Trp3217.43 side chain is shown in sphere.
Fig. 4
Fig. 4. Structural basis for D1R activation by the non-catechol agonist Compound 1.
a Compound1 is a partial agonist of D1R compared to dopamine when tested in Lmtk cells. Dose-dependent cAMP stimulation curves of Compound1 (blue) and dopamine (black) are generated by GraphPad Prism5.0. The curves shown are typical from one experiment with triplicate determinations, repeated at least twice (n = 2). Points and error bars on each curve represent the mean ± SEM. Source data are provided as a Source Data file.b The PIF motif conformation of D1R-Gs (green), β2AR-Gs (gray, PDB ID: 3SN6), β2AR inactive-state (pink, PDB ID: 2RH1) structures. The side chains of residues are shown in stick.c Compound1 (lime) binding to D1R induces a shift in the positions of Phe6.51, Phe6.52, Trp6.48 through its aromatic furo-pyridine ring, relative to the inactive-state position of homologous residues in the β2AR. The dashed arrows indicate estimated residue shift during activation.d The shift of Trp6.48 drives the movement of Phe6.44 to the active conformation, while the shift of Phe6.52 causes Phe5.47 to relocate, creating space for the reorientation of Ile3.40 and Phe6.44 in the active conformation. The dashed arrows indicate estimated residue shift during activation.
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