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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 \u201cAchilles heel\u201d for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable\u00a0D5 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.<\/jats:p>","DOI":"10.1073\/pnas.2300054120","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T13:34:32Z","timestamp":1679405672000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5669-9071","authenticated-orcid":false,"given":"Stefan G.","family":"Krimmer","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 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