PDBsum entry 4qrc

Transferase/transferase inhibitor

PDB id: 4qrc

Contents

Protein chain

297 a.a.

Ligands

SO4 ×4

0LI

Waters ×95

PDB id:

4qrc

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of the tyrosine kinase domain of fgf receptor 4 in complex with ponatinib

Structure:

Fibroblast growth factor receptor 4. Chain: a. Fragment: tyrosine kinase domain of fgf receptor 4. Synonym: fgfr-4. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr4, jtk2, tkf. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.173 R-free: 0.207

Authors:

Z.Huang,M.Mohammadi

Key ref:

Z.Huang et al. (2015). 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. PubMed id: 25317566 DOI: 10.1021/cb500674s

Date:

30-Jun-14 Release date: 29-Oct-14

Protein chain

P22455  (FGFR4_HUMAN) -  Fibroblast growth factor receptor 4 from Homo sapiens

Seq: 802 a.a.

Struc: 297 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/cb500674s

Acs Chem Biol 10:299-309 (2015)

PubMed id: 25317566

DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors.

Z.Huang, L.Tan, H.Wang, Y.Liu, S.Blais, J.Deng, T.A.Neubert, N.S.Gray, X.Li, M.Mohammadi.

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.