Decoupling the dynamic mechanism revealed by FGFR2 mutation-induced population shift

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Fibroblast growth factor receptor 2 (FGFR2) is crucial in cell signaling.
• Dysfunctional FGFR2 activation is linked to cancer and developmental disorders.
• Activation loop (A-loop) mutations may increase FGFR2 kinase activity, but mechanisms remain unclear.

Purpose of the Study:

• To investigate the dynamic molecular mechanisms of FGFR2 activation caused by A-loop mutations.
• To analyze the conformational changes and allosteric communication in FGFR2 mutants.

Main Methods:

• Employed large-scale Gaussian accelerated molecular dynamics simulations for five FGFR2 A-loop mutants (K659E, K659N, K659M, K659Q, K659T).
• Utilized Markov state models to identify conformational states and key residues.
• Applied community network analysis to assess allosteric communication pathways.

Main Results:

• All analyzed FGFR2 mutants exhibited a higher proportion of active-like states compared to wild-type.
• Identified key residues contributing to increased kinase activity.
• Revealed enhanced long-range allosteric communication between the A-loop and hinge region in mutants.

Conclusions:

• FGFR2 A-loop mutations promote a more active conformation through dynamic mechanisms.
• Enhanced allosteric signaling in mutants provides a basis for understanding disease and designing allosteric drugs.
• Findings offer insights into FGFR2's dynamic activation and potential therapeutic strategies.