3UG2

Crystal structure of the mutated EGFR kinase domain (G719S/T790M) in complex with gefitinib

3UG2 の概要

• エントリーDOI: 10.2210/pdb3ug2/pdb
• 関連するPDBエントリー: 2EB2 2EB3 3UG1 3VJN 3VJO
• 分子名称: Epidermal growth factor receptor, Gefitinib, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• 機能のキーワード: kinase, tyrosine-protein kinase, atp binding, phosphorylation, transmembrane, receptor, disease mutation, cell cycle, drug resistance, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 38680.19

構造登録者

Parker, L.J.,Handa, N.,Yoshikawa, S.,Kukimoto-Niino, M.,Shirouzu, M.,Yokoyama, S. (登録日: 2011-11-02, 公開日: 2012-03-07, 最終更新日: 2023-11-01)

主引用文献

Yoshikawa, S.,Kukimoto-Niino, M.,Parker, L.,Handa, N.,Terada, T.,Fujimoto, T.,Terazawa, Y.,Wakiyama, M.,Sato, M.,Sano, S.,Kobayashi, T.,Tanaka, T.,Chen, L.,Liu, Z.J.,Wang, B.C.,Shirouzu, M.,Kawa, S.,Semba, K.,Yamamoto, T.,Yokoyama, S.
Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor
Oncogene, 32:27-38, 2013

PubMed Abstract: The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

PubMed: 22349823
DOI: 10.1038/onc.2012.21

実験手法

X-RAY DIFFRACTION (2.5 Å)