4J23

Low resolution crystal structure of the FGFR2D2D3/FGF1/SR128545 complex

Summary for 4J23

• Entry DOI: 10.2210/pdb4j23/pdb
• Descriptor: Fibroblast growth factor receptor 2, Fibroblast growth factor 1 (2 entities in total)
• Functional Keywords: protein-protein complex, immunoglobulin c-2 type, receptor domain, fgf binding, transferase, protein binding, membrane protein, signaling protein, signaling protein-transferase complex, signaling protein/transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 40630.00

Authors

Kudlinzki, D.,Saxena, K.,Sreeramulu, S.,Schieborr, U.,Dreyer, M.,Schreuder, H.,Schwalbe, H. (deposition date: 2013-02-04, release date: 2014-02-19, Last modification date: 2024-11-06)

Primary citation

Herbert, C.,Schieborr, U.,Saxena, K.,Juraszek, J.,De Smet, F.,Alcouffe, C.,Bianciotto, M.,Saladino, G.,Sibrac, D.,Kudlinzki, D.,Sreeramulu, S.,Brown, A.,Rigon, P.,Herault, J.P.,Lassalle, G.,Blundell, T.L.,Rousseau, F.,Gils, A.,Schymkowitz, J.,Tompa, P.,Herbert, J.M.,Carmeliet, P.,Gervasio, F.L.,Schwalbe, H.,Bono, F.
Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling.
Cancer Cell, 23:489-501, 2013

PubMed Abstract: The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.

PubMed: 23597563
DOI: 10.1016/j.ccr.2013.02.018

Experimental method

X-RAY DIFFRACTION (3.882 Å)