EMD-27411

Single-particle
3.96 Å
EMD-27411 Deposition: 22/06/2022
Map released: 29/03/2023
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-27411

Ectodomain of full-length KIT(T417I,delta418-419)-SCF dimers

EMD-27411

Single-particle
3.96 Å
EMD-27411 Deposition: 22/06/2022
Map released: 29/03/2023
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Full-length KIT(T417I,delta418-419)-SCF dimers reconstituted in amphipol
Fitted models: 8dfq (Avg. Q-score: 0.422)

Deposition Authors: Krimmer SG , Bertoletti N , Mi W , Schlessinger J
Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention.
Krimmer SG , Bertoletti N , Suzuki Y , Katic L, Mohanty J, Shu S, Lee S , Lax I, Mi W , Schlessinger J
(2023) PNAS , 120 , e2300054120 - e2300054120
PUBMED: 36943885
DOI: doi:10.1073/pnas.2300054120
ISSN: 1091-6490
ASTM: PNASA6
Abstract:
The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an "Achilles heel" for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5.