1RY7

Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1

Summary for 1RY7

• Entry DOI: 10.2210/pdb1ry7/pdb
• Related: 1DJS 1EVT 1NUN
• Descriptor: Heparin-binding growth factor 1, Fibroblast growth factor receptor 3 (2 entities in total)
• Functional Keywords: fgf-fgfr complex; beta trefoil; ig domain, growth factor-growth factor receptor complex, growth factor/growth factor receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P05230; Membrane; Single-pass type I membrane protein: P22607
• Total number of polymer chains: 2
• Total formula weight: 53777.13

Authors

Olsen, S.K.,Ibrahimi, O.A.,Raucci, A.,Zhang, F.,Eliseenkova, A.V.,Yayon, A.,Basilico, C.,Linhardt, R.J.,Schlessinger, J.,Mohammadi, M. (deposition date: 2003-12-19, release date: 2004-02-10, Last modification date: 2024-10-30)

Primary citation

Olsen, S.K.,Ibrahimi, O.A.,Raucci, A.,Zhang, F.,Eliseenkova, A.V.,Yayon, A.,Basilico, C.,Linhardt, R.J.,Schlessinger, J.,Mohammadi, M.
Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity.
Proc.Natl.Acad.Sci.Usa, 101:935-940, 2004

PubMed Abstract: The prototypical fibroblast growth factor receptor (FGFR) extracellular domain consists of three Ig domains (D1-D3) of which the two membrane-proximal D2 and D3 domains and the interconnecting D2-D3 linker bear the determinants of ligand binding and specificity. In contrast, D1 and the D1-D2 linker are thought to play autoinhibitory roles in FGFR regulation. Here, we report the crystal structure of the three-Ig form of FGFR3c in complex with FGF1, an FGF that binds promiscuously to each of the seven principal FGFRs. In this structure, D1 and the D1-D2 linker are completely disordered, demonstrating that these regions are dispensable for FGF binding. Real-time binding experiments using surface plasmon resonance show that relative to two-Ig form, the three-Ig form of FGFR3c exhibits lower affinity for both FGF1 and heparin. Importantly, we demonstrate that this autoinhibition is mediated by intramolecular interactions of D1 and the D1-D2 linker with the minimal FGF and heparin-binding D2-D3 region. As in the FGF1-FGFR2c structure, but not the FGF1-FGFR1c structure, the alternatively spliced betaC'-betaE loop is ordered and interacts with FGF1 in the FGF1-FGFR3c structure. However, in contrast to the FGF1-FGFR2c structure in which the betaC'-betaE loop interacts with the beta-trefoil core region of FGF1, in the FGF1-FGFR3c structure, this loop interacts extensively with the N-terminal region of FGF1, underscoring the importance of the FGF1 N terminus in conferring receptor-binding affinity and promiscuity. Importantly, comparison of the three FGF1-FGFR structures shows that the flexibility of the betaC'-betaE loop is a major determinant of ligand-binding specificity and promiscuity.

PubMed: 14732692
DOI: 10.1073/pnas.0307287101

Experimental method

X-RAY DIFFRACTION (3.2 Å)