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-Structure paper
タイトル | Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 120, Issue 13, Page e2300054120, Year 2023 |
掲載日 | 2023年3月28日 |
![]() | Stefan G Krimmer / Nicole Bertoletti / Yoshihisa Suzuki / Luka Katic / Jyotidarsini Mohanty / Sheng Shu / Sangwon Lee / Irit Lax / Wei Mi / Joseph Schlessinger / ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 3.17 - 13.1 Å |
構造データ | EMDB-27408, PDB-8dfm: EMDB-27410, PDB-8dfp: EMDB-27411, PDB-8dfq: ![]() EMDB-27495: Full-length KIT(T417I,delta418-419) dimers ![]() EMDB-27496: Full-length KIT(T417I,delta418-419) dimers |
化合物 | ![]() ChemComp-NAG: |
由来 |
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![]() | TRANSFERASE / receptor tyrosine kinase / cell signaling / cancer / cryo-EM / KIT / stem cell factor / oncogenic mutant / extracellular domain / asymmetric interface / structural plasticity |