4PGZ

Structural basis of KIT activation by oncogenic mutations in the extracellular region reveals a zipper-like mechanism for ligand-dependent or oncogenic receptor tyrosine kinase activation

Summary for 4PGZ

• Entry DOI: 10.2210/pdb4pgz/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit, 2-acetamido-2-deoxy-beta-D-glucopyranose, COBALT (II) ION, ... (4 entities in total)
• Functional Keywords: receptor tyrosine kinase, kit receptor, igsf, cancer, surface receptor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 71050.96

Authors

Reshetnyak, A.V.,Boggon, T.J.,Lax, I.,Schlessinger, J. (deposition date: 2014-05-03, release date: 2015-03-18, Last modification date: 2024-10-09)

Primary citation

Reshetnyak, A.V.,Opatowsky, Y.,Boggon, T.J.,Folta-Stogniew, E.,Tome, F.,Lax, I.,Schlessinger, J.
The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer.
Mol.Cell, 57:191-201, 2015

PubMed Abstract: The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important "driver" role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C-terminal Ig-like domain (D5) of the ectodomain, rendering KIT tyrosine kinase activity constitutively activated. The structural analysis, together with biochemical and biophysical experiments and detailed analyses of the activities of a variety of oncogenic KIT mutations, reveals that the strength of homotypic contacts and the cooperativity in the action of D4D5 regions determines whether KIT is normally regulated or constitutively activated in cancers. We propose that cooperative interactions mediated by multiple weak homotypic contacts between receptor molecules are responsible for regulating normal ligand-dependent or oncogenic RTK activation via a "zipper-like" mechanism for receptor activation.

PubMed: 25544564
DOI: 10.1016/j.molcel.2014.11.021

Experimental method

X-RAY DIFFRACTION (2.4 Å)