National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Elife. 2019 Nov 21;8:e48822. doi: 10.7554/eLife.48822.
Multiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report the 3.5-angstrom crystal structure of mouse dopamine receptor D4 (DRD4) complexed with a subtype-selective antagonist, L745870. Our structure reveals a secondary binding pocket extended from the orthosteric ligand-binding pocket to a DRD4-specific crevice located between transmembrane helices 2 and 3. Additional mutagenesis studies suggest that the antagonist L745870 prevents DRD4 activation by blocking the relative movement between transmembrane helices 2 and 3. These results expand our knowledge of the molecular basis for the physiological functions of DRD4 and assist new drug design.
G 蛋白偶联受体超家族中的多种多巴胺受体亚型通过各种下游信号通路调节神经过程。关于多巴胺受体家族的一个关键问题是，什么结构特征决定了潜在药物的亚型选择性。在这里，我们报告了与亚型选择性拮抗剂 L745870 结合的小鼠多巴胺受体 D4 (DRD4) 的 3.5 埃晶体结构。我们的结构揭示了一个从正位配体结合口袋延伸到位于跨膜螺旋 2 和 3 之间的 DRD4 特异性裂隙的二级结合口袋。额外的突变研究表明，拮抗剂 L745870 通过阻止跨膜螺旋 2 和 3 之间的相对运动来阻止 DRD4 的激活。这些结果扩展了我们对 DRD4 生理功能的分子基础的认识，并有助于新的药物设计。
