2HWP

Crystal structure of Src kinase domain in complex with covalent inhibitor PD168393

2HWP の概要

• エントリーDOI: 10.2210/pdb2hwp/pdb
• 関連するPDBエントリー: 2HWO
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, N-[4-(3-BROMO-PHENYLAMINO)-QUINAZOLIN-6-YL]-ACRYLAMIDE (3 entities in total)
• 機能のキーワード: kinase, covalent, quinazoline, modification, transferase
• 由来する生物種: Gallus gallus (chicken)
• 細胞内の位置: Cell membrane : P00523
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66223.85

構造登録者

Rauh, D.,Blair, J.A.,Shokat, K.M. (登録日: 2006-08-01, 公開日: 2007-02-27, 最終更新日: 2024-10-30)

主引用文献

Blair, J.A.,Rauh, D.,Kung, C.,Yun, C.H.,Fan, Q.W.,Rode, H.,Zhang, C.,Eck, M.J.,Weiss, W.A.,Shokat, K.M.
Structure-guided development of affinity probes for tyrosine kinases using chemical genetics.
Nat.Chem.Biol., 3:229-238, 2007

PubMed Abstract: As key components in nearly every signal transduction pathway, protein kinases are attractive targets for the regulation of cellular signaling by small-molecule inhibitors. We report the structure-guided development of 6-acrylamido-4-anilinoquinazoline irreversible kinase inhibitors that potently and selectively target rationally designed kinases bearing two selectivity elements that are not found together in any wild-type kinase: an electrophile-targeted cysteine residue and a glycine gatekeeper residue. Cocrystal structures of two irreversible quinazoline inhibitors bound to either epidermal growth factor receptor (EGFR) or engineered c-Src show covalent inhibitor binding to the targeted cysteine (Cys797 in EGFR and Cys345 in engineered c-Src). To accommodate the new covalent bond, the quinazoline core adopts positions that are different from those seen in kinase structures with reversible quinazoline inhibitors. Based on these structures, we developed a fluorescent 6-acrylamido-4-anilinoquinazoline affinity probe to report the fraction of kinase necessary for cellular signaling, and we used these reagents to quantitate the relationship between EGFR stimulation by EGF and its downstream outputs-Akt, Erk1 and Erk2.

PubMed: 17334377
DOI: 10.1038/nchembio866

実験手法

X-RAY DIFFRACTION (2.48 Å)