3I2T

Crystal structure of the unliganded Drosophila Epidermal Growth Factor Receptor ectodomain

3I2T の概要

• エントリーDOI: 10.2210/pdb3i2t/pdb
• 分子名称: Epidermal growth factor receptor, isoform A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-alpha-D-glucopyranose, 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: drosophila, egfr, ectodomain, unliganded, autoinhibited, atp-binding, nucleotide-binding, tyrosine-protein kinase, transferase
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65060.16

構造登録者

Alvarado, D.,Klein, D.E.,Lemmon, M.A. (登録日: 2009-06-29, 公開日: 2009-09-08, 最終更新日: 2024-11-06)

主引用文献

Alvarado, D.,Klein, D.E.,Lemmon, M.A.
ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor.
Nature, 461:287-291, 2009

PubMed Abstract: The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

PubMed: 19718021
DOI: 10.1038/nature08297

実験手法

X-RAY DIFFRACTION (2.7 Å)