The extracellular domain (ECD) of class B1 G-protein-coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Although recent studies suggest a role for membrane lipids in the modulation of class A and class F GPCR signaling properties, little is known about the effect of lipids on class B1 receptors. In this study, we employed multiscale molecular dynamics simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers. Simulations showed that the ECD could move about a hinge region formed by residues Q122–E126 to adopt both closed and open conformations relative to the transmembrane domain. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation may affect the ligand binding and receptor activation properties. We also identify a unique phosphatidylinositol (4,5)-bisphosphate (PIP2) interaction profile near intracellular loop (ICL) 2/TM3 at the G-protein-coupling interface, suggesting a mechanism of engaging G-proteins that may have a distinct dependence on PIP2 compared with class A GPCRs. Given the structural conservation of class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting.

中文翻译：

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鞘糖脂 GM3 调节胰高血糖素受体的构象动力学

B1 类 G 蛋白偶联受体 (GPCR) 的细胞外结构域 (ECD) 在信号转导中起着核心作用，并且独特地定​​位于感知细胞外和膜环境。尽管最近的研究表明膜脂在 A 类和 F 类 GPCR 信号传导特性的调节中起作用，但关于脂质对 B1 类受体的影响知之甚少。在这项研究中，我们采用多尺度分子动力学模拟来访问存在天然样膜双层时胰高血糖素受体 (GCGR) ECD 的动力学。模拟表明，ECD 可以围绕由残基 Q122-E126 形成的铰链区移动，以采用相对于跨膜结构域的闭合和开放构象。ECD 运动通过结合鞘糖脂 GM3 进行调节。ECD 构象的这些大规模波动可能会影响配体结合和受体激活特性。我们还在 G 蛋白偶联界面处的细胞内环 (ICL) 2/TM3 附近发现了独特的磷脂酰肌醇 (4,5)-二磷酸 (PIP2) 相互作用谱，表明可能具有明显依赖性的 G 蛋白参与机制在 PIP2 上与 A 类 GPCR 相比。鉴于 B1 类 GPCR 的结构保守性，GM3 和 PIP2 对 GCGR 的调节作用可能在这些受体中是保守的，为潜在的治疗靶向提供了新的见解。表明与 A 类 GPCR 相比，可能对 PIP2 具有明显依赖性的 G 蛋白参与机制。鉴于 B1 类 GPCR 的结构保守性，GM3 和 PIP2 对 GCGR 的调节作用可能在这些受体中是保守的，为潜在的治疗靶向提供了新的见解。表明与 A 类 GPCR 相比，可能对 PIP2 具有明显依赖性的 G 蛋白参与机制。鉴于 B1 类 GPCR 的结构保守性，GM3 和 PIP2 对 GCGR 的调节作用可能在这些受体中是保守的，为潜在的治疗靶向提供了新的见解。