3GRW

FGFR3 in complex with a Fab

Summary for 3GRW

• Entry DOI: 10.2210/pdb3grw/pdb
• Descriptor: Fibroblast growth factor receptor 3, Fab light chain, Fab heavy chain, ... (6 entities in total)
• Functional Keywords: fgfr3, fab, protein-protein complex, receptor tyrosine kinase, atp-binding, immunoglobulin domain, kinase, membrane, nucleotide-binding, receptor, transferase, transmembrane, tyrosine-protein kinase, transferase-immune system complex, transferase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 75436.03

Authors

Wiesmann, C. (deposition date: 2009-03-26, release date: 2009-05-05, Last modification date: 2024-10-30)

Primary citation

Qing, J.,Du, X.,Chen, Y.,Chan, P.,Li, H.,Wu, P.,Marsters, S.,Stawicki, S.,Tien, J.,Totpal, K.,Ross, S.,Stinson, S.,Dornan, D.,French, D.,Wang, Q.R.,Stephan, J.P.,Wu, Y.,Wiesmann, C.,Ashkenazi, A.
Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.
J.Clin.Invest., 119:1216-1229, 2009

PubMed Abstract: Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-A resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.

PubMed: 19381019
DOI: 10.1172/JCI38017

Experimental method

X-RAY DIFFRACTION (2.1 Å)