5VAN

Crystal Structure of Beta-Klotho

5VAN の概要

• エントリーDOI: 10.2210/pdb5van/pdb
• 関連するPDBエントリー: 5VAK 5VAQ
• 分子名称: Beta-klotho, Nb914, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: (beta/alpha)8 receptor for endocrine fgf, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 126435.74

構造登録者

Lee, S.,Schlessinger, J. (登録日: 2017-03-27, 公開日: 2018-01-31, 最終更新日: 2024-11-13)

主引用文献

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

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: 29342135
DOI: 10.1038/nature25010

実験手法

X-RAY DIFFRACTION (2.202 Å)