5VAQ
Crystal Structure of Beta-Klotho in Complex with FGF21CT
Summary for 5VAQ
| Entry DOI | 10.2210/pdb5vaq/pdb |
| Related | 5V9Q 5V9R |
| Descriptor | Beta-klotho, Nb914, Fibroblast growth factor 21, ... (4 entities in total) |
| Functional Keywords | (beta/alpha) 8 receptor for endocrine fgf, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 127050.57 |
| Authors | Lee, S.,Schlessinger, J. (deposition date: 2017-03-27, release date: 2018-01-31, Last modification date: 2024-11-20) |
| Primary citation | Lee, S.,Choi, J.,Mohanty, J.,Sousa, L.P.,Tome, F.,Pardon, E.,Steyaert, J.,Lemmon, M.A.,Lax, I.,Schlessinger, J. Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling. Nature, 553:501-505, 2018 Cited by PubMed Abstract: Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs. PubMed: 29342135DOI: 10.1038/nature25010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.606 Å) |
Structure validation
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