4QQJ

Crystal Structure of FGF Receptor (FGFR) 4 Kinase Domain Harboring the V550L Gate-Keeper Mutation

Summary for 4QQJ

• Entry DOI: 10.2210/pdb4qqj/pdb
• Related: 4QQ5 4QQC 4QQT
• Descriptor: Fibroblast growth factor receptor 4, SULFATE ION (3 entities in total)
• Functional Keywords: kinase domain fold, cell signaling, phosphotransferase, plasmamembrane, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted. Isoform 3: Cytoplasm : P22455
• Total number of polymer chains: 1
• Total formula weight: 36333.66

Authors

Huang, Z.,Mohammadi, M. (deposition date: 2014-06-27, release date: 2014-10-29, Last modification date: 2023-09-20)

Primary citation

Huang, Z.,Tan, L.,Wang, H.,Liu, Y.,Blais, S.,Deng, J.,Neubert, T.A.,Gray, N.S.,Li, X.,Mohammadi, M.
DFG-out Mode of Inhibition by an Irreversible Type-1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors.
Acs Chem.Biol., 10:299-309, 2015

PubMed Abstract: Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN-2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate-keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2.

PubMed: 25317566
DOI: 10.1021/cb500674s

Experimental method

X-RAY DIFFRACTION (1.682 Å)