6BN5

Non-receptor Protein Tyrosine Phosphatase SHP2 F285S in Complex with Allosteric Inhibitor JLR-2

6BN5 の概要

• エントリーDOI: 10.2210/pdb6bn5/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, 3-benzyl-8-chloro-2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one (3 entities in total)
• 機能のキーワード: shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q06124
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121235.48

構造登録者

Blacklow, S.C.,Stams, T.,Fodor, M.,LaRochelle, J.R. (登録日: 2017-11-16, 公開日: 2017-12-13, 最終更新日: 2023-10-04)

主引用文献

LaRochelle, J.R.,Fodor, M.,Ellegast, J.M.,Liu, X.,Vemulapalli, V.,Mohseni, M.,Stams, T.,Buhrlage, S.J.,Stegmaier, K.,LaMarche, M.J.,Acker, M.G.,Blacklow, S.C.
Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
Bioorg. Med. Chem., 25:6479-6485, 2017

PubMed Abstract: The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression.

PubMed: 29089257
DOI: 10.1016/j.bmc.2017.10.025

実験手法

X-RAY DIFFRACTION (2.22 Å)