格拉斯哥大学研究小组取得一项新突破。他们提出了游离脂肪酸受体2的变构调节和偏置信号。相关论文于2025年6月18日发表在《自然》杂志上。

在这里，该课题组报道了FFA2与两个G蛋白质和三种不同类别的正变构调节剂（PAMs），并描述了涉及classGPCRs。两个PAMs破坏E/DRY激活微开关并稳定细胞内环的构象。通过与受体细胞质侧附近的面向脂质的口袋结合。相比之下，第三种PAM促进了跨膜螺旋的分离。6和7与跨膜螺旋相互作用6在受体-脂质界面。分子动力学模拟和诱变实验证实了这些非典型的激活机制。

此外，该研究团队证明了Gi与Gq偏差的分子基础，这是由于细胞内环的不同构象2种不同PAMs稳定；这些发现为定制GPCR调节剂的设计提供了一个框架，其意义超出了FFA2，延伸到更广泛的GPCR药物发现领域。

据介绍，游离脂肪酸受体2 （FFA2）是G蛋白质偶联受体（GPCR），是肠道微生物群产生的短链脂肪酸的主要传感器。因此，FFA2是免疫代谢紊乱的一个有希望的药物靶点。

附：英文原文

Title: Allosteric modulation and biased signalling at free fatty acid receptor 2

Author: Zhang, Xuan, Guseinov, Abdul-Akim, Jenkins, Laura, Valentini, Alice, Marsango, Sara, Schultz-Knudsen, Katrine, Ulven, Trond, Rexen Ulven, Elisabeth, Tikhonova, Irina G., Milligan, Graeme, Zhang, Cheng

Issue&Volume: 2025-06-18

Abstract: Free fatty acid receptor2 (FFA2) is a Gprotein-coupled receptor (GPCR) that is a primary sensor for short-chain fatty acids produced by gut microbiota. Consequently, FFA2 is a promising drug target for immunometabolic disorders1,2,3,4. Here we report cryogenic electronic microscopy structures of FFA2 in complex with two Gproteins and three distinct classes of positive allosteric modulators (PAMs), and describe noncanonical activation mechanisms that involve conserved structural features of classA GPCRs. Two PAMs disrupt the E/DRY activation microswitch5 and stabilize the conformation of intracellular loop2 by binding to lipid-facing pockets near the cytoplasmic side of the receptor. By contrast, the third PAM promotes the separation of transmembrane helices6 and 7 by interacting with transmembrane helix6 at the receptor–lipid interface. Molecular dynamic simulations and mutagenesis experiments confirm these noncanonical activation mechanisms. Furthermore, we demonstrate the molecular basis for the Gi versus Gq bias, which is due to distinct conformations of intracellular loop2 stabilized by different PAMs. These findings provide a framework for the design of tailored GPCR modulators, with implications that extend beyond FFA2 to the broader field of GPCR drug discovery.

DOI: 10.1038/s41586-025-09186-6

Source: https://www.nature.com/articles/s41586-025-09186-6