6H8S

CRYSTAL STRUCTURE OF THE MOUSE PROTEIN TYROSINE PHOSPHATASE PTPN5 (STEP) IN COMPLEX WITH COMPOUND BI-0314

6H8S の概要

• エントリーDOI: 10.2210/pdb6h8s/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 5, 1-[3-piperidin-4-yl-5-(trifluoromethyl)phenyl]guanidine (3 entities in total)
• 機能のキーワード: protein phosphatase, ptn5, step, allosteric modulator, hydrolase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35166.87

構造登録者

Fiegen, D.,Schnapp, G. (登録日: 2018-08-03, 公開日: 2018-09-26, 最終更新日: 2024-01-17)

主引用文献

Tautermann, C.S.,Binder, F.,Buttner, F.H.,Eickmeier, C.,Fiegen, D.,Gross, U.,Grundl, M.A.,Heilker, R.,Hobson, S.,Hoerer, S.,Luippold, A.,Mack, V.,Montel, F.,Peters, S.,Bhattacharya, S.,Vaidehi, N.,Schnapp, G.,Thamm, S.,Zeeb, M.
Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule.
J. Med. Chem., 62:306-316, 2019

PubMed Abstract: Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases. We report the discovery of the first small molecule allosteric activator for STEP that binds to the phosphatase domain. Allosteric binding is confirmed by both X-ray and N NMR experiments, and specificity has been demonstrated by an enzymatic test cascade. Molecular dynamics simulations indicate stimulation of enzymatic activity by a long-range allosteric mechanism. To allow the scientific community to make use of this tool, we offer to provide the compound in the course of an open innovation initiative.

PubMed: 30207464
DOI: 10.1021/acs.jmedchem.8b00857

実験手法

X-RAY DIFFRACTION (1.771 Å)