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Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
500
Allosteric changes in the conformational landscape of Src kinase upon substrate binding
Song-Ho Chong1, Hiraku Oshima2, Yuji Sugita3
1Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan; Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Journal of Molecular Biology
|November 20, 2024
Summary
Peptide substrate binding to Src tyrosine kinase unexpectedly promotes transitions to inactive states. This finding clarifies kinase regulation mechanisms and disease implications.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Protein kinase activity is critical for cellular functions.
- Dysregulation of protein kinases is linked to various diseases.
- Conformational changes regulate kinase activity but mechanisms are unclear.
Purpose of the Study:
- To predict the binding mode of peptide substrates to Src tyrosine kinase.
- To investigate allosteric conformational changes upon substrate binding.
- To elucidate the residue-contact network mediating these changes.
Main Methods:
- Enhanced conformational sampling simulations (24 μs) to predict substrate binding.
- Unbiased molecular dynamics simulations (50 μs) on apo and substrate-bound forms.
- Analysis of conformational landscape and residue-contact networks.
Main Results:
- Peptide substrate binding significantly facilitates transitions to inactive kinase conformations.
- Observed changes include outward αC helix, broken regulatory spine, and perturbed ATP-binding domain.
- Identified a residue-contact network responsible for allosteric regulation.
Conclusions:
- Substrate binding can allosterically inhibit Src tyrosine kinase activity.
- Results align with experimental data on negative cooperativity in tyrosine kinases.
- Findings advance understanding of kinase regulation and disease mechanisms.
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