Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, Spain.
Laboratory of Advanced Microscopy (LMA), University of Zaragoza, Zaragoza, Spain.
Nat Commun. 2024 Sep 5;15(1):7759. doi: 10.1038/s41467-024-51993-4.
Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
虽然胺能 GPCR 是约 25%已批准药物的靶点，但由于其正构结合位点的高度序列保守性，开发亚型选择性药物是一个主要挑战。双位配体通过共价键将正构和变构药效基团连接在一起，具有提高受体选择性和通过减少非靶标副作用来改善现有药物的潜力。然而，由于缺乏关于其结合模式的结构信息，合理设计受到阻碍。在这里，我们确定了与 DR 选择性双位激动剂 FOB02-04A 结合的 hDR:Gαβγ 复合物的冷冻电镜结构。结构、功能和计算分析提供了对其结合模式的深入了解，并指出了一个新的 TM2-ECL1-TM1 区域，该区域需要 TM1 的 N 端有序，这是胺能 GPCR 中亚型选择性的主要决定因素。该区域在药物开发中未得到充分利用，扩展了胺能 GPCR 中已建立的次要结合口袋，并且可能被用于设计新型和亚型选择性药物。
