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Updated: Jul 28, 2025
Following the Dynamics of Structural Variants in Experimentally Evolved Populations
Published on: February 3, 2023
Decoupling the dynamic mechanism revealed by FGFR2 mutation-induced population shift
Yuxiang Zhang1, Xiao-Lan Yin2, Mingfei Ji3
1Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
The fibroblast growth factor receptor 2 (FGFR2) is a key component in cellular signaling networks, and its dysfunctional activation has been implicated in various diseases including cancer and developmental disorders. Mutations at the activation loop (A-loop) have been suggested to trigger an increased basal kinase activity. However, the molecular mechanism underlying this highly dynamic process has not been fully understood due to the limitation of static structural information. Here, we conducted multiple, large-scale Gaussian accelerated molecular dynamics simulations of five (K659E, K659N, K659M, K659Q, and K659T) FGFR2 mutants at the A-loop, and comprehensively analyzed the dynamic molecular basis of FGFR2 activation. The results quantified the population shift of each system, revealing that all mutants had a higher proportion of active-like states. Using Markov state models, we extracted the representative structure of different conformational states and identified key residues related to the increased kinase activity. Furthermore, community network analysis showed enhanced information connections in the mutants, highlighting the long-range allosteric communication between the A-loop and the hinge region. Our findings may provide insights into the dynamic mechanism for FGFR2 dysfunctional activation and allosteric drug discovery.Communicated by Ramaswamy H. Sarma.
Insights
Fibroblast growth factor receptor 2 (FGFR2) mutations increase its kinase activity by shifting its conformation. Molecular dynamics simulations reveal enhanced allosteric communication in FGFR2 mutants, offering insights for drug discovery.
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.
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