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. 2022 Jun 8;13:3186. doi: 10.1038/s41467-022-30929-w

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a Surface view of the tavapadon binding pocket. Tavapadon is shown as sticks, and EM density is shown for tavapadon. b Interactions between tavapadon and the receptor. c Structural comparison between the tavapadon- and fenoldopam-bound D1R. d Effect of D1R mutants on the ability of tavapadon to stimulate the production of cAMP. Three independent experiments were repeated for each construct. Data are presented as mean values ± SEM. p values were calculated by means of two-tailed Student’s t test (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). The exact p values are as follows, D103V, ***p = 0.0005; N292L, ****p = 0.00002; S202A, p = 0.7662; S198G, p = 0.1421; F288A, ****p = 0.000046; F289A, ****p = 0.000006; F313A, ***p = 0.0002; W99F, **p = 0.0055; K81V, ****p = 6.2E-07; D314S, p = 0.0785; L190A, ****p = 9.2E−07; S188A, *p = 0.0477; S188I, **p = 0.0015. e Structural overlay of the tavapadon-bound D1R complex and PW0464-bound D1R complex; the receptors are aligned. f Close-up view of the ligand-binding pocket. Concentration-response curves for D1R WT and the S198G mutant activated by tavapadon measured using the NanoBiT (g) and TANGO (h) β-arrestin recruitment assay and the cAMP accumulation assay (i). Each data point represents mean ± SEM from three independent experiments. Source data are provided as a Source Date file.