ConfometRx, Inc., Santa Clara, CA, USA.
UCB Pharma, Braine-l'Alleud, Belgium.
Nat Commun. 2021 Jun 3;12(1):3305. doi: 10.1038/s41467-021-23519-9.
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.
多巴胺 D1 受体（D1R）是一种重要的药物靶点，与许多精神和神经疾病有关。人们希望选择性激动 D1R 成为这些疾病的治疗策略。大多数选择性 D1R 激动剂在其分子结构中都具有多巴胺样儿茶酚部分，因此它们的治疗潜力受到体内不良药理学性质的限制。最近，报道了一类具有独特支架和药理学性质的非儿茶酚 D1R 选择性激动剂。在这里，我们报告了 D1R 与刺激 G 蛋白（Gs）和非儿茶酚激动剂化合物 1 复合物的晶体结构，分辨率为 3.8Å。该结构揭示了配体以伸展构象与 D1R 结合，从正位结合点延伸到细胞外环 2（ECL2）。结构分析表明，D1R 配体结合口袋的独特特征解释了该支架对 D1R 的显著选择性，超过了其他单胺能受体，并且阐明了非儿茶酚激动剂激活 D1R 的机制。
