4O3U

Zymogen HGF-beta/MET with Zymogen Activator Peptide ZAP2.3

4O3U の概要

• エントリーDOI: 10.2210/pdb4o3u/pdb
• 分子名称: Hepatocyte growth factor, Hepatocyte growth factor receptor, ZAP 2.3 (3 entities in total)
• 機能のキーワード: trypsin homoloy, receptor activation, transferase-growth factor complex, transferase/growth factor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P14210
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 91301.14

構造登録者

Eigenbrot, C.,Landgraf, K.E.,Steffek, M. (登録日: 2013-12-18, 公開日: 2014-06-04, 最終更新日: 2024-10-09)

主引用文献

Landgraf, K.E.,Steffek, M.,Quan, C.,Tom, J.,Yu, C.,Santell, L.,Maun, H.R.,Eigenbrot, C.,Lazarus, R.A.
An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides.
Nat.Chem.Biol., 10:567-573, 2014

PubMed Abstract: Stimulation of hepatocyte growth factor (HGF) signaling through the Met receptor is an attractive approach for promoting tissue repair and preventing fibrosis. Using structure-guided peptide phage display combined with an activity-based sorting strategy, we engineered allosteric activators of zymogen-like pro-HGF to bypass proteolytic activation and reversibly stimulate pro-HGF signaling through Met. Biochemical, structural and biological data showed that zymogen activator peptides (ZAPtides) potently and selectively bind the activation pocket within the serine protease-like β-chain of pro-HGF and display titratable activation of pro-HGF-dependent Met signaling, leading to cell survival and migration. To further demonstrate the versatility of our ZAPtide platform, we identified allosteric activators for pro-macrophage stimulating protein and a zymogen serine protease, Protein C, which also provides evidence for target selectivity. These studies reveal that ZAPtides use molecular mimicry of the trypsin-like N-terminal insertion mechanism and establish a new paradigm for selective pharmacological activation of plasminogen-related growth factors and zymogen serine proteases.

PubMed: 24859116
DOI: 10.1038/nchembio.1533

実験手法

X-RAY DIFFRACTION (3.04 Å)