1XKK

EGFR kinase domain complexed with a quinazoline inhibitor- GW572016

1XKK の概要

• エントリーDOI: 10.2210/pdb1xkk/pdb
• 分子名称: Epidermal growth factor receptor, PHOSPHATE ION, N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE, ... (4 entities in total)
• 機能のキーワード: egfr, epidermal growth factor receptor, kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41095.41

構造登録者

Wood, E.R.,Truesdale, A.T.,McDonald, O.B.,Yuan, D.,Hassell, A.,Dickerson, S.H.,Ellis, B.,Pennisi, C.,Horne, E.,Lackey, K.,Alligood, K.J.,Rusnak, D.W.,Gilmer, T.M.,Shewchuk, L.M. (登録日: 2004-09-29, 公開日: 2004-12-07, 最終更新日: 2023-08-23)

主引用文献

Wood, E.R.,Truesdale, A.T.,McDonald, O.B.,Yuan, D.,Hassell, A.,Dickerson, S.H.,Ellis, B.,Pennisi, C.,Horne, E.,Lackey, K.,Alligood, K.J.,Rusnak, D.W.,Gilmer, T.M.,Shewchuk, L.
A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells.
Cancer Res., 64:6652-6659, 2004

PubMed Abstract: GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.

PubMed: 15374980
DOI: 10.1158/0008-5472.CAN-04-1168

実験手法

X-RAY DIFFRACTION (2.4 Å)