PDBsum entry 4qqt

Transferase

PDB id: 4qqt

Contents

Protein chain

283 a.a.

Ligands

SO4 ×2

References listed in PDB file

Key reference

• Title: Dfg-Out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-Keeper mutations in fgf receptors.
• Authors: Z.Huang, L.Tan, H.Wang, Y.Liu, S.Blais, J.Deng, T.A.Neubert, N.S.Gray, X.Li, M.Mohammadi.
• Ref.: Acs Chem Biol, 2015, 10, 299-309. [DOI no: 10.1021/cb500674s]
• PubMed id: 25317566

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.