School of Pharmaceutical Science, Wenzhou Medical University, Center for Cancer and Metabolism Research, Institute for Life Science, Wenzhou University, Wenzhou, Zhejiang 325000, China; Proteomics and Nanotechnology Laboratory, Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA; Current address: Centeer BioTherapeutics Ltd Co., Houston, TX 77021, USA.
School of Life Science, Tianjin University, Tianjin 300072, China; Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Huangzhou, Zhejiang 310058, China.
Trends Pharmacol Sci. 2019 Feb;40(2):142-153. doi: 10.1016/j.tips.2018.12.002. Epub 2019 Jan 4.
Endocrine fibroblast growth factors (eFGFs) control pathways that are crucial for maintaining metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Unlike the heparin-binding paracrine FGFs, eFGFs require a unique Klotho family protein to form a productive triad complex, but the structural and mechanistical details of this complex have remained obscure since the beginning of the eFGF field. However, recent breakthroughs in resolving the 3D structures of eFGF signaling complexes have now unveiled the atomic details of multivalent interactions among eFGF, FGFR, and Klotho. We provide here a timely review on the architecture and the structure-function relationships of these complexes, and highlight how the structural knowledge opens a new door to structure-based drug design against a repertoire of eFGF-associated metabolic diseases.
内分泌成纤维细胞生长因子（eFGFs）控制着对维持脂质、葡萄糖、能量、胆汁酸和矿物质代谢稳态至关重要的途径。与肝素结合的旁分泌 FGFs 不同，eFGFs 需要一种独特的 Klotho 家族蛋白形成有产性的三联体复合物，但自 eFGF 领域开始以来，该复合物的结构和机械细节仍不清楚。然而，最近在解决 eFGF 信号转导复合物的三维结构方面的突破，现在揭示了 eFGF、FGFR 和 Klotho 之间多价相互作用的原子细节。我们在这里提供了对这些复合物的结构和功能关系的及时综述，并强调了结构知识如何为针对一系列与 eFGF 相关的代谢疾病的基于结构的药物设计开辟了新的途径。
