Department of Chemistry, Stanford University, Stanford, CA, USA.
Department of Computer Science, Stanford University, Stanford, CA, USA.
Nat Commun. 2024 Nov 16;15(1):9938. doi: 10.1038/s41467-024-54103-6.
The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate the signaling of G-protein-coupled receptors (GPCRs), the largest class of drug targets. Decades of research have led to the widely accepted view that all agonists-ligands that trigger GPCR activation-function by causing rearrangement of the GPCR's transmembrane helices, opening an intracellular pocket for binding of transducer proteins. Here we demonstrate that certain agonists instead trigger activation of free fatty acid receptor 1 by directly rearranging an intracellular loop that interacts with transducers. We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations that disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate the signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets.
设计更安全、更有效的药物的目标促使人们对配体如何精确地操纵 G 蛋白偶联受体 (GPCR) 的信号转导的分子机制产生了浓厚的兴趣，GPCR 是最大的一类药物靶点。数十年的研究得出了一个被广泛接受的观点，即所有激动剂——触发 GPCR 激活的配体——通过引起 GPCR 的跨膜螺旋重排而起作用，为转导蛋白的结合打开细胞内口袋。在这里，我们证明某些激动剂通过直接重排与转导蛋白相互作用的细胞内环来触发游离脂肪酸受体 1 的激活。我们通过靶向突变验证了我们原子水平模拟的预测；破坏与细胞内环相互作用的特定突变将这些激动剂转化为反向激动剂。进一步的分析表明，变构配体可以通过类似的机制调节许多其他 GPCR 的信号转导，为精确控制药物靶点提供了丰富的可能性。
