4I22

Structure of the monomeric (V948R)gefitinib/erlotinib resistant double mutant (L858R+T790M) EGFR kinase domain co-crystallized with gefitinib

4I22 の概要

• エントリーDOI: 10.2210/pdb4i22/pdb
• 関連するPDBエントリー: 4I1Z 4I20 4I21 4I23 4I24
• 分子名称: Epidermal growth factor receptor, Gefitinib, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase domain, phosphotrasfer, atp binding, 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: 38219.48

構造登録者

Gajiwala, K.S.,Feng, J.,Ferre, R.,Ryan, K.,Brodsky, O.,Stewart, A. (登録日: 2012-11-21, 公開日: 2013-01-16, 最終更新日: 2024-03-27)

主引用文献

Gajiwala, K.S.,Feng, J.,Ferre, R.,Ryan, K.,Brodsky, O.,Weinrich, S.,Kath, J.C.,Stewart, A.
Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition.
Structure, 21:209-219, 2013

PubMed Abstract: The oncogenicity of the L858R mutant form of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is thought to be due to the constitutive activation of its kinase domain. The selectivity of the marketed drugs gefitinib and erlotinib for L858R mutant is attributed to their specific recognition of the active kinase and to weaker ATP binding by L858R EGFR. We present crystal structures showing that neither L858R nor the drug-resistant L858R+T790M EGFR kinase domain is in the constitutively active conformation. Additional co-crystal structures show that gefitinib and dacomitinib, an irreversible anilinoquinazoline derivative currently in clinical development, may not be conformation specific for the active state of the enzyme. Structural data further reveal the potential mode of recognition of one of the autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase domain. Biochemical and biophysical evidence suggest that the oncogenic mutations impact the conformational dynamics of the enzyme.

PubMed: 23273428
DOI: 10.1016/j.str.2012.11.014

実験手法

X-RAY DIFFRACTION (1.71 Å)