Extended Data Fig. 7: Structural features of fenoldopam- or A77636-bound hTAAR1.

a, Screening of 22 synthetic molecules for hTAAR1 activation, as assessed using the Glosensor assay. At the administration of 10 μM, two of the 22 compounds showed >50% of activity of agonist β-PEA and SEP-363856. Data shown as mean ± standard error of the mean (SEM) (n = 4 biologically independent samples). ***P < 0.001. Comparison between buffer and several ligands. All the data were determined by one-way of variance ANOVA with Dunnett’s test (From left to right, P = < 0.001, <0.001, <0.001, <0.001, 0.999, 0.265, > 0.999, > 0.999, 0.988, > 0.999, 0.999, 0.995, 0.999, 0.971, 0.969, > 0.999, 0.994, 0.994, > 0.999, > 0.999, > 0.999, 0.988, 0.948, > 0.999). b, Representative dose-response curves for hTAAR1-Gs signalling simulated by the endogenous agonist β-PEA, as well as SEP-363856, fenoldopam, and A77636, as determined by the CAMYEL assay. All curves are mean ± SEM of three independent experiments performed in triplicate (n = 3). c, d, Activation potency and efficacy of hTAAR1 and mTAAR1 induced by β-PEA, fenoldopam and A77636 using CAMYEL assay. Data are presented as mean ± SEM of three independent experiments performed in triplicate. e, f, Structural details of fenoldopam (magenta, stick) (e) and A77636 (orange, stick) (f) bound to hTAAR1. Schematic representation of residues contacts with fenoldopam and A77636 in hTAAR1. Residues in pocket 1, 2 and 4 are shown in pink boxes, green boxes and medium slate blue boxes, respectively. Residues located concurrently in pocket 2 and pocket 4 are placed in a green/medium slate blue mixed box. g, Different binding pose of fenoldopam in the structure between DRD1 and hTAAR1. h, Structural comparison of fenoldopam-DRD1 with A77636-hTAAR1.