7EMN

The atomic structure of SHP2 E76A mutant

「6IHZ」から置き換えられました

7EMN の概要

• エントリーDOI: 10.2210/pdb7emn/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11 (2 entities in total)
• 機能のキーワード: phosphatase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 122780.52

構造登録者

Luo, F.,Xie, J.J.,Zhu, J.D.,Liu, C. (登録日: 2021-04-14, 公開日: 2021-05-05, 最終更新日: 2023-11-29)

主引用文献

Tao, Y.,Xie, J.,Zhong, Q.,Wang, Y.,Zhang, S.,Luo, F.,Wen, F.,Xie, J.,Zhao, J.,Sun, X.,Long, H.,Ma, J.,Zhang, Q.,Long, J.,Fang, X.,Lu, Y.,Li, D.,Li, M.,Zhu, J.,Sun, B.,Li, G.,Diao, J.,Liu, C.
A novel partially open state of SHP2 points to a "multiple gear" regulation mechanism.
J.Biol.Chem., 296:100538-100538, 2021

PubMed Abstract: The protein tyrosine phosphatase SHP2 mediates multiple signal transductions in various cellular pathways, controlled by a variety of upstream inputs. SHP2 dysregulation is causative of different types of cancers and developmental disorders, making it a promising drug target. However, how SHP2 is modulated by its different regulators remains largely unknown. Here, we use single-molecule fluorescence resonance energy transfer and molecular dynamics simulations to investigate this question. We identify a partially open, semiactive conformation of SHP2 that is intermediate between the known open and closed states. We further demonstrate a "multiple gear" regulatory mechanism, in which different activators (e.g., insulin receptor substrate-1 and CagA), oncogenic mutations (e.g., E76A), and allosteric inhibitors (e.g., SHP099) can shift the equilibrium of the three conformational states and regulate SHP2 activity to different levels. Our work reveals the essential role of the intermediate state in fine-tuning the activity of SHP2, which may provide new opportunities for drug development for relevant cancers.

PubMed: 33722610
DOI: 10.1016/j.jbc.2021.100538

実験手法

X-RAY DIFFRACTION (3 Å)