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Published on: May 20, 2020
Molecular dynamics simulations reveal phosphorylation-induced conformational dynamics of the fibroblast growth factor
Subhasmita Mahapatra1, Nisha Amarnath Jonniya1, Suman Koirala1
1Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India.
Abstract:
The Fibroblast Growth Factor Receptor1 (FGFR1) kinase wields exquisite control on cell fate, proliferation, differentiation, and homeostasis. An imbalance of FGFR1 signaling leads to several pathogeneses of diseases ranging from multiple cancers to allergic and neurodegenerative disorders. In this study, we investigated the phosphorylation-induced conformational dynamics of FGFR1 in apo and ATP-bound states via all-atom molecular dynamics simulations. All simulations were performed for 2 × 2 µs. We have also investigated the energetics of the binding of ATP to FGFR1 using the molecular mechanics Poisson-Boltzmann scheme. Our study reveals that the FGFR1 kinase can reach a fully active configuration through phosphorylation and ATP binding. A 3-10 helix formation in the activation loop signifies its rearrangement leading to stability upon ATP binding. The interaction of phosphorylated tyrosine (pTyr654) with positively charged residues forms strong salt-bridge interactions, driving the compactness of the structure. The dynamic cross-correlation map reveals phosphorylation enhances correlated motions and reduces anti-correlated motions between different domains. We believe that the mechanistic understanding of large-conformational changes upon the activation of the FGFR1 kinase will aid the development of novel targeted therapeutics.Communicated by Ramaswamy H. Sarma.
Insights
Fibroblast Growth Factor Receptor1 (FGFR1) kinase activation involves conformational changes upon phosphorylation and ATP binding. This molecular insight into FGFR1 dynamics aids targeted therapeutic development for related diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Fibroblast Growth Factor Receptor1 (FGFR1) kinase is crucial for cell regulation.
- Dysregulated FGFR1 signaling contributes to cancers, allergic, and neurodegenerative diseases.
Purpose of the Study:
- To investigate the phosphorylation-induced conformational dynamics of FGFR1.
- To understand the energetics of ATP binding to FGFR1.
Main Methods:
- All-atom molecular dynamics simulations (2 × 2 µs).
- Molecular mechanics Poisson-Boltzmann scheme for binding energetics.
Main Results:
- FGFR1 achieves full activity through phosphorylation and ATP binding.
- Phosphorylation and ATP binding stabilize FGFR1 via 3-10 helix formation in the activation loop.
- Phosphorylated tyrosine (pTyr654) forms salt bridges, enhancing structural compactness.
- Phosphorylation increases correlated motions and reduces anti-correlated motions between FGFR1 domains.
Conclusions:
- Phosphorylation and ATP binding induce significant conformational changes in FGFR1.
- Understanding FGFR1 activation mechanisms can guide novel therapeutic strategies.
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