ArticlePLoS computational biology2011
Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 77 citations in OpenAlex.
- Targeted Therapy for Advanced Gastrointestinal Stromal Tumors: Evolution and Future Directions.Drug design, development and therapy · 2026Review
- Well-differentiated systemic mastocytosis: Genetics, mast cell immunophenotypes, and KIT autophosphorylation.The Journal of allergy and clinical immunology · 2025Article
- Article
- Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study.International journal of molecular sciences · 2023Article
- Avapritinib for the treatment of KIT mutation-negative systemic mastocytosis.Proceedings (Baylor University. Medical Center) · 2023Article
- Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia withAnnals of laboratory medicine · 2022Article
- Mutations responsible for the carbapenemase activity of SME-1.RSC advances · 2022Article
- Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis.International journal of molecular sciences · 2021Review
- Case Report: Evolution ofFrontiers in oncology · 2021Article
- Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy.International journal of molecular sciences · 2020Review
- The Spectrum of Aggressive Mastocytosis: A Workshop Report and Literature Review.Pathobiology : journal of immunopathology, molecular and cellular biology · 2020Review
- Systemic Mastocytosis: Following the Tyrosine Kinase Inhibition Roadmap.Frontiers in pharmacology · 2020Review
- "Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.Scientific reports · 2018Article
- KIT Suppresses BRAFCancer research · 2017Article
- Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17Oncotarget · 2017Article
- Co-occurrence ofBlood advances · 2017Article
- Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome.Journal of proteomics · 2016Article
- Dissecting protein architecture with communication blocks and communicating segment pairs.BMC bioinformatics · 2016Article
- Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of the Native and Mutated CSF-1R and KIT.PloS one · 2016Article
- Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours.PLoS genetics · 2015Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites.
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