5JKG

The crystal structure of FGFR4 kinase domain in complex with LY2874455

Summary for 5JKG

• Entry DOI: 10.2210/pdb5jkg/pdb
• Descriptor: Fibroblast growth factor receptor 4, 2-[4-[E-2-[5-[(1R)-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1H-indazol-3-yl]ethenyl]pyrazol-1-yl]ethanol (3 entities in total)
• Functional Keywords: kinase, small-molecule inhibitor, atp binding pocket, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 35135.39

Authors

Wu, D.,Chen, L.,Chen, Y. (deposition date: 2016-04-26, release date: 2016-10-05, Last modification date: 2024-03-20)

Primary citation

Wu, D.,Guo, M.,Philips, M.A.,Qu, L.,Jiang, L.,Li, J.,Chen, X.,Chen, Z.,Chen, L.,Chen, Y.
Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455
Plos One, 11:e0162491-e0162491, 2016

PubMed Abstract: Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.

PubMed: 27618313
DOI: 10.1371/journal.pone.0162491

Experimental method

X-RAY DIFFRACTION (2.352 Å)