研究人员利用原型肾上腺素-β2肾上腺素能受体-G蛋白系统来揭示了特定受体残基如何解码和翻译配体中编码的信息以介导信号反应。研究人员提出了一个数据科学框架，用于整合药理学和结构数据，并揭示与配体药理学相关的结构变化和异位网络。这些方法可用于研究任何配体-受体-信号系统，其原理为设计具有明确信号特性的正构和异构化合物提供了可能性。
据了解，异三聚鸟嘌呤核苷酸结合蛋白（G蛋白）偶联受体（GPCR）与细胞外配体和药物结合，并通过构象变化调节细胞内反应。尽管它们是重要的药物靶点，但对于任何配体-受体-信号系统来说，药效（最大信号反应）和药力（半最大反应时的配体浓度）等药理特性的分子起源仍然知之甚少。
附：英文原文
Title: Molecular determinants of ligand efficacy and potency in GPCR signaling
Author: Franziska M. Heydenreich, Maria Marti-Solano, Manbir Sandhu, Brian K. Kobilka, Michel Bouvier, M. Madan Babu
Issue&Volume: 2023-12-22
Abstract: Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline–β2 adrenergic receptor–G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.
DOI: adh1859
Source: https://www.science.org/doi/10.1126/science.adh1859