G蛋白偶联受体变构调节的应用模型

Operational models of allosteric modulation of G protein-coupled receptors

自50年前Monod、Wyman及Changeux最先提出用以解释酶学中蛋白及配体相互作用的变构调控学说以来,已经产生包括诱导-契合在内的多个调控模型及学说。随着生命科学的发展,这些理论被广泛应用于变构酶以及受体的变构调节现象研究中。Lefkowitz研究团队于1980年提出了揭示G蛋白偶联受体工作机制的三元复合体模型,为研究这一最大受体家族的变构调节位点和相关配体奠定了理论基础。着眼于配体与受体结合进而调控受体活化状态及功能的基础研究,已经对药物研发产生了重要的影响,并将进一步推动新型变构调节剂的开发。

Since the Monod-Wyman-Changeux（MWC） model was initially proposed to explain the allosteric interactions between proteins and their ligands 50 years ago, there have been various models and hypotheses such as the induced-fit model on the interaction. These theoretical developments have been used broadly in the study of allosteric modulations of enzymes and receptors. In 1980, Lefkowitz and coworkers proposed a ternary complex model（TCM） for the regulatory mechanism of G protein-coupled receptors（GPCRs） that laid the theoretical foundation in the study of allosteric sites and ligands of GPCRs, the largest family of known receptors. The findings on how ligands interact with receptors to cause a functional response have significantly impacted the drug discovery field and accelerated the identification of allosteric modulators.