受体酪氨酸激酶KIT及其配体干细胞因子（SCF）对造血干细胞、生殖细胞和其他细胞的发育至关重要。一系列人类癌症（如急性髓细胞白血病、胃肠道间质瘤和肥大细胞白血病）都由体细胞获得性KIT突变所驱动。本文报道了采用冷冻电镜（cryo-EM）结构分析技术分析了全长野生型和两个癌变型KIT突变体的结果，结果表明配体结合的KIT双聚体的细胞外结构具有对称性，其中包含了不对称的D5同型接触点，紧贴于细胞质膜上。KIT的突变分析表明D5区域是治疗干预的“关键点”。经过配体敏感的KIT突变体展示了一个更全面稳定的D5不对称构象。一个配体非依赖的KIT突变体则采用由D5介导的接触点构形的“V”形状。SCF与该突变体的结合可以完全恢复野生型KIT双聚体的构形，包括D4同型接触的盐桥形成与SCF诱导的KIT双聚体的其他特征。这些实验揭示了肿瘤性KIT突变体的一个出乎意料的结构可塑性以及D5领域的治疗靶点。

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.