6XL4

EGFR(T790M/V948R) in complex with AZD9291 and DDC4002

6XL4 の概要

• エントリーDOI: 10.2210/pdb6xl4/pdb
• 分子名称: Epidermal growth factor receptor, ~{N}-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide, 10-benzyl-8-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, ... (6 entities in total)
• 機能のキーワード: cancer, chemotherapy, kinase inhibitors, allosteric, 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: 4
• 化学式量合計: 152406.25

構造登録者

Heppner, D.E.,Beyett, T.S.,Eck, M.J. (登録日: 2020-06-28, 公開日: 2021-06-30, 最終更新日: 2024-11-06)

主引用文献

Beyett, T.S.,To, C.,Heppner, D.E.,Rana, J.K.,Schmoker, A.M.,Jang, J.,De Clercq, D.J.H.,Gomez, G.,Scott, D.A.,Gray, N.S.,Janne, P.A.,Eck, M.J.
Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors.
Nat Commun, 13:2530-2530, 2022

PubMed Abstract: Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.

PubMed: 35534503
DOI: 10.1038/s41467-022-30258-y

実験手法

X-RAY DIFFRACTION (2.06 Å)