6OB2

Crystal structure of wild-type KRAS (GMPPNP-bound) in complex with GAP-related domain (GRD) of neurofibromin (NF1)

Summary for 6OB2

• Entry DOI: 10.2210/pdb6ob2/pdb
• Descriptor: GTPase KRas, Neurofibromin, GLYCEROL, ... (8 entities in total)
• Functional Keywords: kras, ras, kras4b, nf1, gap, neurofibromin, gtp binding-lipid binding complex, gtp binding/lipid binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 98523.05

Authors

Tran, T.H.,Dharmaiah, S.,Simanshu, D.K. (deposition date: 2019-03-19, release date: 2019-10-16, Last modification date: 2023-10-11)

Primary citation

Rabara, D.,Tran, T.H.,Dharmaiah, S.,Stephens, R.M.,McCormick, F.,Simanshu, D.K.,Holderfield, M.
KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis.
Proc.Natl.Acad.Sci.USA, 116:22122-22131, 2019

PubMed Abstract: mutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render -mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that G13-mutated cancer cells are frequently comutated with GAP but is rarely mutated in cancers with codon 12 or 61 mutations. Neurofibromin protein (encoded by the gene) hydrolyzes GTP directly in complex with KRAS G13D, and G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset of G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.

PubMed: 31611389
DOI: 10.1073/pnas.1908353116

Experimental method

X-RAY DIFFRACTION (2.845 Å)