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A shift of dynamic equilibrium between the {KIT} active and inactive states causes drug resistance
- Source :
- Proteins: Structure, Function, and Bioinformatics, Proteins, United States
- Publication Year :
- 2020
-
Abstract
- Tyrosine phosphorylation, a highly regulated post-translational modification, is carried out by the enzyme tyrosine kinase (TK). TKs are important mediators in signaling cascades, facilitating diverse biological processes in response to stimuli. TKs may acquire mutations leading to malignancy and are viable targets for anti-cancer drugs. Mast/stem cell growth factor receptor KIT is a TK involved in cell differentiation, whose dysregulation leads to various types of cancer, including gastrointestinal stromal tumors, leukemia, and melanoma. KIT can be targeted by a range of inhibitors that predominantly bind to the inactive state of the enzyme. A mutation Y823D in the activation loop of KIT is known to be responsible for the loss of sensitivity to some drugs in metastatic tumors. We used all-atom molecular dynamics simulations to study the impact of Y823D on the KIT conformation and dynamics and compared it to the effect of phosphorylation of Y823. We simulated in total 6.4 μs of wild-type, mutant and phosphorylated KIT in the active- and inactive-state conformations. We found that Y823D affects the protein dynamics differently: in the active state, the mutation increases the protein stability, whereas in the inactive state it induces local destabilization, thus shifting the dynamic equilibrium towards the active state, altering the communication between distant regulatory regions. The observed dynamics of the Y823D mutant is similar to the dynamics of KIT phosphorylated at position Y823, thus we hypothesize that this mutation mimics a constitutively active kinase, which is not responsive to inhibitors that bind its inactive conformation.
- Subjects :
- Protein Conformation, alpha-Helical
Mutant
Antineoplastic Agents
Molecular Dynamics Simulation
Ligands
Biochemistry
Substrate Specificity
03 medical and health sciences
chemistry.chemical_compound
Structural Biology
Humans
cancer
Protein Interaction Domains and Motifs
Phosphorylation
mutation Y823D
Databases, Protein
Receptor
Protein Kinase Inhibitors
Molecular Biology
030304 developmental biology
chemistry.chemical_classification
Aspartic Acid
0303 health sciences
Binding Sites
Protein Stability
Kinase
030302 biochemistry & molecular biology
Hydrogen Bonding
Tyrosine phosphorylation
molecular dynamics simulations
secondary resistance
KIT tyrosine kinase
Cell biology
Proto-Oncogene Proteins c-kit
Enzyme
chemistry
Drug Resistance, Neoplasm
Mutation
Thermodynamics
Tyrosine
Protein Conformation, beta-Strand
Signal transduction
Protein Processing, Post-Translational
Tyrosine kinase
signal transduction
Protein Binding
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Proteins: Structure, Function, and Bioinformatics, Proteins, United States
- Accession number :
- edsair.doi.dedup.....d65e08868710437c2c6ef0ba046b38b7