5WB8

Crystal structure of the epidermal growth factor receptor extracellular region in complex with epigen

5WB8 の概要

• エントリーDOI: 10.2210/pdb5wb8/pdb
• 分子名称: Epidermal growth factor receptor, Epigen, 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 tyrosine kinase, growth factor, signaling, membrane protein, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129970.76

構造登録者

Bessman, N.J.,Freed, D.M.,Moore, J.O.,Ferguson, K.M.,Lemmon, M.A. (登録日: 2017-06-28, 公開日: 2017-10-18, 最終更新日: 2024-10-23)

主引用文献

Freed, D.M.,Bessman, N.J.,Kiyatkin, A.,Salazar-Cavazos, E.,Byrne, P.O.,Moore, J.O.,Valley, C.C.,Ferguson, K.M.,Leahy, D.J.,Lidke, D.S.,Lemmon, M.A.
EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.
Cell, 171:683-695.e18, 2017

PubMed Abstract: Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF-making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G-protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.

PubMed: 28988771
DOI: 10.1016/j.cell.2017.09.017

実験手法

X-RAY DIFFRACTION (3 Å)