7TYD

Crystal structure of FGFR4 domain 3 in complex with a de novo-designed mini-binder in P21 space group

Summary for 7TYD

• Entry DOI: 10.2210/pdb7tyd/pdb
• Related: 7N1J
• Descriptor: Fibroblast growth factor receptor 4, Binder (3 entities in total)
• Functional Keywords: receptor tyrosine kinase, complex, binder, membrane protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 43615.39

Authors

Park, J.S.,Lee, S. (deposition date: 2022-02-12, release date: 2022-11-09, Last modification date: 2023-10-18)

Primary citation

Park, J.S.,Choi, J.,Cao, L.,Mohanty, J.,Suzuki, Y.,Park, A.,Baker, D.,Schlessinger, J.,Lee, S.
Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein.
Cell Rep, 41:111545-111545, 2022

PubMed Abstract: 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.

PubMed: 36288716
DOI: 10.1016/j.celrep.2022.111545

Experimental method

X-RAY DIFFRACTION (2.86 Å)