7LFS

Crystal structure of the epidermal growth factor receptor extracellular region with A265V mutation in complex with epiregulin

7LFS の概要

• エントリーDOI: 10.2210/pdb7lfs/pdb
• 関連するPDBエントリー: 7LEN
• 分子名称: Isoform 4 of Epidermal growth factor receptor, Proepiregulin, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: receptor, epiregulin, glioblastoma, cancer, mutation, extracellular, asymmetric, dimer, erbb1, egfr, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 253030.76

構造登録者

Hu, C.,Leche II, C.A.,Stayrook, S.E.,Ferguson, K.M.,Lemmon, M.A. (登録日: 2021-01-18, 公開日: 2021-11-17, 最終更新日: 2024-11-06)

主引用文献

Hu, C.,Leche 2nd, C.A.,Kiyatkin, A.,Yu, Z.,Stayrook, S.E.,Ferguson, K.M.,Lemmon, M.A.
Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias.
Nature, 602:518-522, 2022

PubMed Abstract: The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer, and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor, but not in glioblastoma multiforme (GBM), where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands. Different growth factor ligands stabilize distinct EGFR dimer structures that signal with different kinetics to specify or bias outcome. EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation. GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting.

PubMed: 35140400
DOI: 10.1038/s41586-021-04393-3

実験手法

X-RAY DIFFRACTION (3.5 Å)