School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), and Curtin Institute for Computation, Curtin University, Bentley, Western Australia, Australia.
Org Biomol Chem. 2020 Dec 28;18(48):9816-9825. doi: 10.1039/d0ob02175j. Epub 2020 Dec 8.
The Class F G protein-coupled receptors (GPCRs) include Smoothened and the ten Frizzled receptors, which are major cell membrane receptors in the Hedgehog and Wnt signalling pathways respectively and of enormous interest in embryonic development and as therapeutic targets in cancer. Recent crystal structures of Smoothened provide the opportunity to investigate the structural biology of Class F GPCRs in more detail, in turn, informing the development of therapeutics. A key question in this area is how one receptor may trigger distinct pathways - particularly relevant for Wnt signalling, in which signals may be transduced from a Frizzled via Dishevelled or G proteins, depending on the context. In this study, we employ adiabatic biased molecular dynamics and umbrella sampling to investigate the activation of Smoothened and Frizzled-7 in both the native state and bound to endogenous ligands, as well as how the clinically used Smoothened antagonist vismodegib alters this signalling. The results highlight key energetic barriers in the activation of these receptors, and the molecular features of the receptors mediating these barriers, demonstrating our approach as a robust means of investigating signalling through these receptors.
F 类 G 蛋白偶联受体（GPCR）包括 Smoothened 和十个 Frizzled 受体，它们分别是 Hedgehog 和 Wnt 信号通路中的主要细胞膜受体，在胚胎发育中具有巨大的研究价值，并且是癌症治疗的重要靶点。Smoothened 的最新晶体结构为更详细地研究 F 类 GPCR 的结构生物学提供了机会，从而为治疗药物的开发提供了信息。该领域的一个关键问题是一个受体如何触发不同的途径 - 对于 Wnt 信号特别相关，其中信号可以通过 Dishevelled 或 G 蛋白从 Frizzled 转导，具体取决于上下文。在这项研究中，我们采用非绝热偏置分子动力学和伞状采样来研究 Smoothened 和 Frizzled-7 在天然状态和与内源性配体结合时的激活情况，以及临床使用的 Smoothened 拮抗剂维莫德吉如何改变这种信号转导。研究结果突出了这些受体激活过程中的关键能量障碍，以及介导这些障碍的受体的分子特征，证明了我们的方法是研究这些受体信号转导的一种稳健手段。
