Fig. 4: Structural basis for D1R activation by the non-catechol agonist Compound 1.

a Compound 1 is a partial agonist of D1R compared to dopamine when tested in Lmtk cells. Dose-dependent cAMP stimulation curves of Compound 1 (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 Compound 1 (lime) binding to D1R induces a shift in the positions of Phe^6.51, Phe^6.52, Trp^6.48 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 Trp^6.48 drives the movement of Phe^6.44 to the active conformation, while the shift of Phe^6.52 causes Phe^5.47 to relocate, creating space for the reorientation of Ile^3.40 and Phe^6.44 in the active conformation. The dashed arrows indicate estimated residue shift during activation.