1T49

Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

1T49 の概要

• エントリーDOI: 10.2210/pdb1t49/pdb
• 関連するPDBエントリー: 1PTY 1T48 1T4J 2HNP
• 分子名称: Protein-tyrosine phosphatase, non-receptor type 1, MAGNESIUM ION, 3-(3,5-DIBROMO-4-HYDROXY-BENZOYL)-2-ETHYL-BENZOFURAN-6-SULFONIC ACID (4-SULFAMOYL-PHENYL)-AMIDE, ... (4 entities in total)
• 機能のキーワード: allosteric inhibition, protein tyrosine phosphatase 1b, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35403.21

構造登録者

Wiesmann, C.,Barr, K.J.,Kung, J.,Zhu, J.,Shen, W.,Fahr, B.J.,Zhong, M.,Taylor, L.,Randal, M.,McDowell, R.S.,Hansen, S.K. (登録日: 2004-04-28, 公開日: 2004-07-20, 最終更新日: 2024-02-14)

主引用文献

Wiesmann, C.,Barr, K.J.,Kung, J.,Zhu, J.,Erlanson, D.A.,Shen, W.,Fahr, B.J.,Zhong, M.,Taylor, L.,Randal, M.,McDowell, R.S.,Hansen, S.K.
Allosteric inhibition of protein tyrosine phosphatase 1B.
Nat.Struct.Mol.Biol., 11:730-737, 2004

PubMed Abstract: Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

PubMed: 15258570
DOI: 10.1038/nsmb803

実験手法

X-RAY DIFFRACTION (1.9 Å)