基于双头分子策略的Smoothened受体作用机制的研究

Smoothened（SMO）受体属于G蛋白偶联受体中的F家族，在介导和控制细胞分化的过程中具有重要意义，是Hedgehog信号通路相关癌症治疗的热门靶点。SMO受体的跨膜域、胞外域以及多结构域整体结构已分别获得解析，但是各功能域之间的相互作用机制尚未明晰。本项目拟设计和开发由跨膜域和胞外域各自配体链接而成的新型双头（bitopic）工具分子，通过考察配体与受体之间的结合模式（单边结合或同时结合），分析配体的作用模式（拮抗、激活、部分激活和反向激活等），归纳这些工具分子结构与生物活性之间的关系， 推导SMO受体的胞外域与跨膜域之间的互动机理。本项目的实施有助于进一步理解SMO受体在Hedgehog通路中的信号转导角色，为相关疾病的药物开发提供理性的新思路。

Smoothened receptor (SMO), one of the Frizzled (Class F) G protein-coupled receptors, plays an essential role in regulating cell differentiation. SMO has been a promising drug target for cancer therapeutics in the context of Hedgehog signaling pathway. Structural studies have been progressed on the determination of its extracellular domain (ECD), transmembrane domain (TMD) and multi-domain, respectively, while the mechanistic understanding of domain-domain communication remain to be fully explored. In this proposal is provided a strategy to design and apply novel bitopic tool compounds comprised of ligands from each domain. To this end, we are going to investigate the binding modes between bitopic ligands and SMO receptor (either simultaneously or not), and analyze the functions of ligands (e.g. agonist, antagonist, partial agonist or reverse agonist). Taken together, these results shall reflect a clear structure-activity relationship (SAR) of the bitopic compounds from which to address the above issues. This project will further the understanding of the role of SMO receptor in the Hedgehog signaling pathway through which rational design of novel drugs can be expected.