5OW1

X-Ray Characterization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors

5OW1 の概要

• エントリーDOI: 10.2210/pdb5ow1/pdb
• 関連するPDBエントリー: 5OVR 5OVX
• 分子名称: Tyrosine-protein phosphatase non-receptor type 5, [[3-(3-cyclohexyl-2-oxidanyl-phenyl)phenyl]-bis(fluoranyl)methyl]phosphonic acid (3 entities in total)
• 機能のキーワード: phosphatase, alzheimer's disease, inhibitor, ptpn5, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Multi-pass membrane protein : P54829
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35619.25

構造登録者

Kack, H.,Wissler, L. (登録日: 2017-08-30, 公開日: 2017-11-22, 最終更新日: 2024-11-06)

主引用文献

Witten, M.R.,Wissler, L.,Snow, M.,Geschwindner, S.,Read, J.A.,Brandon, N.J.,Nairn, A.C.,Lombroso, P.J.,Kack, H.,Ellman, J.A.
X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors.
J. Med. Chem., 60:9299-9319, 2017

PubMed Abstract: Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with K values as low as 7.8 μM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a K of 110 nM, with 15-60-fold selectivity across a series of phosphatases.

PubMed: 29116812
DOI: 10.1021/acs.jmedchem.7b01292

実験手法

X-RAY DIFFRACTION (2.05 Å)