Powers Alexander S, Khan Aasma, Paggi Joseph M, Latorraca Naomi R, Souza Sarah, Salvo Jerry Di, Lu Jun, Soisson Stephen M, Johnston Jennifer M, Weinglass Adam B, Dror Ron O
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
bioRxiv. 2023 Aug 15:2023.08.14.553154. doi: 10.1101/2023.08.14.553154.
The goal of designing safer, more effective drugs has led to tremendous interest in molecular mechanisms through which ligands can precisely manipulate 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 which disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets.
设计更安全、更有效的药物药物这药物的目标，引发了人们对分子机制的极大兴趣，通过这些机制，配体可以精确调控G蛋白偶联受体（GPCRs）的信号传导，GPCRs是最大的一类药物靶点。数十年的研究形成了被广泛接受的观点，即所有激动剂——触发GPCR激活的配体——通过引起GPCR跨膜螺旋的重排来发挥作用，从而打开一个细胞内口袋以结合转导蛋白。在此，我们证明某些激动剂反而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。我们通过定点诱变验证了原子水平模拟的预测结果；破坏与细胞内环相互作用的特定突变会将这些激动剂转变为反向激动剂。进一步分析表明，变构配体可能通过类似机制调控许多其他GPCRs的信号传导，为精确控制药学上重要的靶点提供了丰富的可能性。
