Abstract:
Background: Fibroblast Growth Factor Receptors (FGFRs) are a hotspot for mutations,
with FGFR-targeted therapies approved for bladder cancer, making mutation-specific
signaling crucial to understand.
Objective: To evaluate the impact of less prevalent FGFR3b R248C and FGFR4 G388R
mutations on downstream adaptors via in-silico interaction dynamics.
Methodology: Wildtype and mutant FGFR dimers were modeled with mutations
introduced via DynaMut, then docked with FRS-adaptors using HADDOCK, and
interactions analyzed with PDBSum.
Results: FGFR3b R248C and FGFR4 G388R were found to be slightly stabilized, with
FGFR3b exhibiting increased flexibility and stable fluctuations (0-0.5 Å), while FGFR4
remained rigid with minimal flexibility change (0-0.1 Å); both mutants displayed enhanced
inter-atomic interactions. FGFR3b R248C-FRS2 complex exhibited a lower HADDOCK
score (85.6±36.6 kcal/mol), an increased van der Waals energy (-136.4±10.8 kcal/mol),
along with increased total interacting residues (291) compared to wildtype. R248C-FRS3
complex showed lower HADDOCK (-250.8±20.3 kcal/mol) and van der Waals (-
143.5±22.5 kcal/mol) scores, with increased total interacting residues (250) compared to
wildtype. FGFR4 G388R-FRS2 complex exhibited a higher HADDOCK score (-187.9±7.8
vs. -232.7±3.4 kcal/mol) with negligible changes in van der Waals energies and an increase
in total interacting residues (227 vs. 169) compared to wildtype. G388R-FRS3 complex
also exhibited a higher HADDOCK (-211.2±1.5 vs. -273.4±2.8 kcal/mol) and van der Waals (-121.5±3.8 vs. -148.9±2.7 kcal/mol) scores, with fewer total interacting residues
(188 vs. 220) compared to wildtype.
Conclusion: FGFR3b R248C and FGFR4 G388R mutations were slightly stabilizing.
FGFR3b R248C mutation showed an increased binding affinity with stronger interactions
with both FRS2 and FRS3, while FGFR4 G388R exhibited decreased binding affinity for
FRS2 and FRS3, with changes in interactions. Experimental validation is required to
confirm the impact on downstream oncogenic pathways and therapeutics.
Keywords: Cancer, Fibroblast Growth Factor Receptor 3, Fibroblast Growth Factor
Receptor 4, Molecular Docking.
