3W2O

EGFR Kinase domain T790M/L858R Mutant with TAK-285

3W2O の概要

• エントリーDOI: 10.2210/pdb3w2o/pdb
• 関連するPDBエントリー: 3POZ 3W2P 3W2Q 3W2R 3W2S
• 分子名称: Epidermal growth factor receptor, N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide (3 entities in total)
• 機能のキーワード: anti-oncogene, cell cycle, disease mutation, kinase domain, receptor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38568.93

構造登録者

Sogabe, S.,Kawakita, Y.,Igaki, S. (登録日: 2012-12-03, 公開日: 2013-01-16, 最終更新日: 2023-11-08)

主引用文献

Sogabe, S.,Kawakita, Y.,Igaki, S.,Iwata, H.,Miki, H.,Cary, D.R.,Takagi, T.,Takagi, S.,Ohta, Y.,Ishikawa, T.
Structure-Based Approach for the Discovery of Pyrrolo[3,2-d]pyrimidine-Based EGFR T790M/L858R Mutant Inhibitors.
Acs Med.Chem.Lett., 4:201-205, 2013

PubMed Abstract: The epidermal growth factor receptor (EGFR) family plays a critical role in vital cellular processes and in various cancers. Known EGFR inhibitors exhibit distinct antitumor responses against the various EGFR mutants associated with nonsmall-cell lung cancer. The L858R mutation enhances clinical sensitivity to gefitinib and erlotinib as compared with wild type and reduces the relative sensitivity to lapatinib. In contrast, the T790M mutation confers drug resistance to gefitinib and erlotinib. We determined crystal structures of the wild-type and T790M/L858R double mutant EGFR kinases with reversible and irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285 and neratinib. In these structures, M790 adopts distinct conformations to accommodate different inhibitors, whereas R858 allows conformational variations of the activation loop. These results provide structural insights for understanding the structure-activity relationships that should contribute to the development of potent inhibitors against drug-sensitive or -resistant EGFR mutations.

PubMed: 24900643
DOI: 10.1021/ml300327z

実験手法

X-RAY DIFFRACTION (2.35 Å)