4QL3

Crystal Structure of a GDP-bound G12R Oncogenic Mutant of Human GTPase KRas

Summary for 4QL3

• Entry DOI: 10.2210/pdb4ql3/pdb
• Related: 4LDJ 4OBE 4TQ9 4TQA 4WA7
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: small gtpase, signal transduction, gdp binding, gtp binding, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 1
• Total formula weight: 19896.46

Authors

Hunter, J.C.,Manandhar, A.,Gurbani, D.,Chen, Z.,Westover, K.D. (deposition date: 2014-06-10, release date: 2015-06-10, Last modification date: 2024-02-28)

Primary citation

Hunter, J.C.,Manandhar, A.,Carrasco, M.A.,Gurbani, D.,Gondi, S.,Westover, K.D.
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations.
Mol Cancer Res., 13:1325-1335, 2015

PubMed Abstract: KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by X-ray crystallography. High-resolution X-ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRAS-driven tumors that preferentially signal through RAF.

PubMed: 26037647
DOI: 10.1158/1541-7786.MCR-15-0203

Experimental method

X-RAY DIFFRACTION (1.041 Å)