Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Cell Rep. 2022 Oct 25;41(4):111545. doi: 10.1016/j.celrep.2022.111545.
Cellular signaling by fibroblast growth factor receptors (FGFRs) is a highly regulated process mediated by specific interactions between distinct subsets of fibroblast growth factor (FGF) ligands and two FGFR isoforms generated by alternative splicing: an epithelial b- and mesenchymal c-isoforms. Here, we investigate the properties of a mini-protein, mb7, developed by an in silico design strategy to bind to the ligand-binding region of FGFR2. We describe structural, biophysical, and cellular analyses demonstrating that mb7 binds with high affinity to the c-isoforms of FGFR, resulting in inhibition of cellular signaling induced by a subset of FGFs that preferentially activate c-isoforms of FGFR. Notably, as mb7 blocks interaction between FGFR with Klotho proteins, it functions as an antagonist of the metabolic hormones FGF19 and FGF21, providing mechanistic insights and strategies for the development of therapeutics for diseases driven by aberrantly activated FGFRs.
成纤维细胞生长因子受体 (FGFRs) 的细胞信号转导是一个高度调控的过程，由特定的成纤维细胞生长因子 (FGF) 配体亚群与通过选择性剪接产生的两种 FGFR 同工型之间的特异性相互作用介导：上皮 b-和间充质 c-同工型。在这里，我们研究了一种由计算机设计策略开发的小蛋白 mb7 的特性，该蛋白设计用于结合 FGFR2 的配体结合区域。我们描述了结构、生物物理和细胞分析，证明 mb7 与 FGFR 的 c 同工型具有高亲和力结合，导致对优先激活 FGFR c 同工型的一组 FGF 诱导的细胞信号转导的抑制。值得注意的是，由于 mb7 阻断 FGFR 与 Klotho 蛋白之间的相互作用，因此它作为代谢激素 FGF19 和 FGF21 的拮抗剂发挥作用，为异常激活的 FGFR 驱动的疾病的治疗药物的开发提供了机制见解和策略。
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