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.
FIG: 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.
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
Sun, B., Feng, D., Chu, M.LH. et al. Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist. Nat Commun 12, 3305 (2021). https://doi.org/10.1038/s41467-021-23519-9