4RDD

Co-crystal structure of SHP2 in complex with a Cefsulodin derivative

4RDD の概要

• エントリーDOI: 10.2210/pdb4rdd/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, 1-({(2R)-4-carboxy-2-[(R)-carboxy{[(2R)-2-phenyl-2-sulfoacetyl]amino}methyl]-3,6-dihydro-2H-1,3-thiazin-5-yl}methyl)pyr idinium (3 entities in total)
• 機能のキーワード: hydrolase, 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: 1
• 化学式量合計: 32655.06

構造登録者

Zhang, Z.Y.,Yu, Z.H.,He, R.,Zhang, R.Y. (登録日: 2014-09-18, 公開日: 2015-07-01, 最終更新日: 2024-12-25)

主引用文献

He, R.,Yu, Z.H.,Zhang, R.Y.,Wu, L.,Gunawan, A.M.,Lane, B.S.,Shim, J.S.,Zeng, L.F.,He, Y.,Chen, L.,Wells, C.D.,Liu, J.O.,Zhang, Z.Y.
Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.
ACS Med Chem Lett, 6:782-786, 2015

PubMed Abstract: Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.

PubMed: 26191366
DOI: 10.1021/acsmedchemlett.5b00118

実験手法

X-RAY DIFFRACTION (1.601 Å)