5W59

Crystal structure of a monomeric human FGF9 in complex with the ectodomain of human FGFR1c

Summary for 5W59

• Entry DOI: 10.2210/pdb5w59/pdb
• Related: 1CVS 3OJV
• Descriptor: Fibroblast growth factor 9, Fibroblast growth factor receptor 1, SULFATE ION, ... (4 entities in total)
• Functional Keywords: growth factor, growth factor receptor, ligand-receptor complex, cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 45718.81

Authors

Mohammadi, M.,Ma, J.,Liu, Y. (deposition date: 2017-06-14, release date: 2017-08-16, Last modification date: 2024-11-13)

Primary citation

Liu, Y.,Ma, J.,Beenken, A.,Srinivasan, L.,Eliseenkova, A.V.,Mohammadi, M.
Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization.
Structure, 25:1325-1336.e3, 2017

PubMed Abstract: The epithelial fibroblast growth factor 9 (FGF9) subfamily specifically binds and activates the mesenchymal "c" splice isoform of FGF receptors 1-3 (FGFR1-3) to regulate organogenesis and tissue homeostasis. The unique N and C termini of FGF9 subfamily ligands mediate a reversible homodimerization that occludes major receptor binding sites within the ligand core region. Here we provide compelling X-ray crystallographic, biophysical, and biochemical data showing that homodimerization controls receptor binding specificity of the FGF9 subfamily by keeping the concentration of active FGF9 monomers at a level, which is sufficient for a normal FGFR "c" isoform binding/signaling, but is insufficient for an illegitimate FGFR "b" isoform binding/signaling. We show that deletion of the N terminus or alanine substitutions in the C terminus of FGF9 skews the delicate ligand equilibrium toward active FGF9 monomers causing off-target binding and activation of FGFR b isoforms. Our study is the first to implicate ligand homodimerization in the regulation of ligand-receptor specificity.

PubMed: 28757146
DOI: 10.1016/j.str.2017.06.016

Experimental method

X-RAY DIFFRACTION (2.498 Å)