6OB3

Crystal structure of G13D-KRAS (GMPPNP-bound) in complex with GAP-related domain (GRD) of neurofibromin (NF1)

6OB3 の概要

• エントリーDOI: 10.2210/pdb6ob3/pdb
• 分子名称: GTPase KRas, Neurofibromin, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: kras, ras, kras4b, nf1, gap, neurofibromin, g13d, signaling protein-gtp binding complex, signaling protein/gtp binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 99432.94

構造登録者

Tran, T.H.,Dharmaiah, S.,Simanshu, D.K. (登録日: 2019-03-19, 公開日: 2019-10-16, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)