7TVD

Crystal structure of the kinase domain of EGFR exon-19 (del-747-749) mutant

7TVD の概要

• エントリーDOI: 10.2210/pdb7tvd/pdb
• 分子名称: Epidermal growth factor receptor (1 entity in total)
• 機能のキーワード: egfr, exon-19, kinase, oncoprotein, transferase
• 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: 38237.19

構造登録者

Ashtekar, K.D.,Stayrook, S.E.,Lemmon, M.A. (登録日: 2022-02-04, 公開日: 2022-02-16, 最終更新日: 2023-10-25)

主引用文献

van Alderwerelt van Rosenburgh, I.K.,Lu, D.M.,Grant, M.J.,Stayrook, S.E.,Phadke, M.,Walther, Z.,Goldberg, S.B.,Politi, K.,Lemmon, M.A.,Ashtekar, K.D.,Tsutsui, Y.
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.
Nat Commun, 13:6791-6791, 2022

PubMed Abstract: Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low K). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

PubMed: 36357385
DOI: 10.1038/s41467-022-34398-z

実験手法

X-RAY DIFFRACTION (2.96 Å)