Fig 1.
Structure of LY2874455 in complex with FGFR4.
A: Overall structure of LY2874455/FGFR4 complex. B: The diagram of LY2874455. C: Fo-Fc omit map of LY2874455 in the FGFR4/LY2874455 complex. The electron density is superimposed with the final model. D: The DFG motif conformation of FGFR4. Active ApoFGFR4 DFG-in conformation is shown in blue (PDB: 4QQT); FGFR4/Ponatinib DFG-out conformation is shown in yellow (PDB: 4UXQ); FGFR4/BLU9931 DFG-in conformation is shown in pink (PDB: 4XCU); FGFR4/LY2874455 DFG-in conformation is shown in grey (this work). LY2874455 is highlighted in brown.
Table 1.
Data collection and refinement statistics.
Fig 2.
The interactions of LY2874455 with FGFR4.
A: Schematic diagram of protein-ligand interactions in FGFR4/LY2874455 complex. Hydrogen bonds are indicated by dashed lines between the atoms involved, while hydrophobic contacts are represented by an arc with spokes. The diagram was generated by PDBsum. B: The binding conformation of FGFR4 in complex with LY2874455. The side chain conformations of twelve residues interacting with LY2874455. C: LY2874455 binds in the ATP-binding cavity of FGFR4 with three hydrogen bonds. D: The hydrophobic contacts between LY2874455 and Leu619 of FGFR4.
Fig 3.
Alignment of 4 FGFR kinase domain sequences.
Residues forming hydrogen bonds with LY2874455 are highlighted in black boxes; Residues forming hydrophobic contacts with LY2874455 are highlighted with black arrows. Nonconserved residues in the ATP-binding pocket of FGFRs are highlighted with black triangles.
Fig 4.
Molecular interactions of LY2874455 with 4 FGFRs.
Structural superimposition of FGFR4/LY2874455 complex with other FGFR/drug complexes. A: The similarity of twelve-amino acid side chains of 4 FGFRs interacting with LY2874455. B: The hydrogen bond-binding sites of LY2874455 to FGFR4 are identical to the corresponding sites of FGFR1-3. Hydrogen bonds are shown in black dashed lines. C: The conformation of hydrophobic residue Leu619 in C-lobe of FGFR4 contacts with LY2874455 are conserved in FGFR1-3. D: The similar hydrophobic contacts between LY2874455 and FGFR nonconserved residues. Hydrophobic contacts are shown in red dashed lines. FGFR4 is shown in light grey; ApoFGFR1 is shown in blue (PDB: 4UWY); FGFR2 is shown in pink (PDB: 2PSQ); FGFR3 is shown in yellow (PDB: 4K33); FGFR4 is shown in grey (our data). Inhibitor LY2874455 is highlighted in brown.