8DFM

Ectodomain of full-length wild-type KIT-SCF dimers

8DFM の概要

• エントリーDOI: 10.2210/pdb8dfm/pdb
• EMDBエントリー: 27408
• 分子名称: Isoform 2 of Mast/stem cell growth factor receptor Kit, Soluble KIT ligand, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: receptor tyrosine kinase, cell signaling, cancer, cryo-em, kit, stem cell factor, oncogenic mutant, extracellular domain, asymmetric interface, structural plasticity, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 255468.65

構造登録者

Krimmer, S.G.,Bertoletti, N.,Mi, W.,Schlessinger, J. (登録日: 2022-06-22, 公開日: 2023-03-29, 最終更新日: 2024-11-06)

主引用文献

Krimmer, S.G.,Bertoletti, N.,Suzuki, Y.,Katic, L.,Mohanty, J.,Shu, S.,Lee, S.,Lax, I.,Mi, W.,Schlessinger, J.
Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention.
Proc.Natl.Acad.Sci.USA, 120:e2300054120-e2300054120, 2023

PubMed 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.

PubMed: 36943885
DOI: 10.1073/pnas.2300054120

実験手法

ELECTRON MICROSCOPY (3.45 Å)