2QQ7

Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor

2QQ7 の概要

• エントリーDOI: 10.2210/pdb2qq7/pdb
• 関連するPDBエントリー: 2HWP 2QI8 2QIG 2QLQ
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, (2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide (3 entities in total)
• 機能のキーワード: src kinase domain, drug resistance, irreversible inhibitor, alternative splicing, atp-binding, lipoprotein, myristate, nucleotide-binding, phosphorylation, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• 由来する生物種: Gallus gallus (chicken)
• 細胞内の位置: Cell membrane (By similarity): P00523
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66398.22

構造登録者

Michalczyk, A.,Rode, H.B.,Gruetter, C.,Rauh, D. (登録日: 2007-07-26, 公開日: 2008-03-11, 最終更新日: 2024-10-16)

主引用文献

Michalczyk, A.,Kluter, S.,Rode, H.B.,Simard, J.R.,Grutter, C.,Rabiller, M.,Rauh, D.
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.
Bioorg.Med.Chem., 16:3482-3488, 2008

PubMed Abstract: Resistance to kinase-targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.

PubMed: 18316192
DOI: 10.1016/j.bmc.2008.02.053

実験手法

X-RAY DIFFRACTION (2.38 Å)