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Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight
1a Human Genetics Foundation , via Nizza 52, Torino , I-10126 , Italy .
Abstract:
KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.
Insights
The D816H mutation in KIT receptor alters its extended A-loop dynamics, potentially explaining Sunitinib resistance in gastrointestinal stromal tumors (GISTs). This finding aids in developing new therapies for resistant GIST cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- KIT receptor is a key therapeutic target in gastrointestinal stromal tumors (GISTs).
- Sunitinib, a second-generation inhibitor, targets an inactive KIT conformation to prevent tumor growth.
- Understanding resistance mechanisms is crucial for effective GIST therapy.
Purpose of the Study:
- To investigate the dynamic behavior of wild-type and D816H mutant KIT receptor, focusing on the extended A-loop (EAL) region.
- To elucidate the molecular mechanisms underlying Sunitinib resistance in KIT-driven GISTs.
Main Methods:
- Conducted molecular dynamics simulations (∼100 ns) of wild-type and D816H mutant KIT receptor.
- Analyzed structural properties including RMSD, RMSF, radius of gyration, SASA, and hydrogen bonding.
- Utilized clustering and cross-correlation matrix approaches to explore conformational dynamics of the EAL region.
Main Results:
- The D816H mutation significantly altered intramolecular hydrogen bonding and increased the structural flexibility of the KIT EAL region.
- Flexible secondary structures (coils and turns) predominated in the mutant EAL region, enhancing its mobility.
- This increased EAL region movement shifted the equilibrium towards an active kinase conformation.
Conclusions:
- The D816H mutation promotes KIT activation by increasing EAL region flexibility, contributing to Sunitinib resistance.
- This atomic-level insight into KIT dynamics provides a basis for developing novel therapeutics against resistant GISTs.
