Emerging Structure–Function Paradigm of Endocrine FGFs in Metabolic Diseases

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.