7KH8

Human LMPTP in complex with inhibitor

7KH8 の概要

• エントリーDOI: 10.2210/pdb7kh8/pdb
• 分子名称: Low molecular weight phosphotyrosine protein phosphatase, 3-[(2,6-dichlorophenyl)methyl]-8-(2-methylphenyl)-3H-purin-6-amine, NITRATE ION, ... (4 entities in total)
• 機能のキーワード: protein tyrosine phosphatase, lmwptp, inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36609.01

構造登録者

Stanford, S.M.,Diaz, M.A.,Ardecky, R.J.,Zou, J.,Roosild, T.,Holmes, Z.J.,Hedrick, M.P.,Rodiles, S.,Santelli, E.,Chung, T.D.Y.,Jackson, M.R.,Bottini, N.,Pinkerton, A.B. (登録日: 2020-10-20, 公開日: 2021-05-19, 最終更新日: 2023-10-18)

主引用文献

Stanford, S.M.,Diaz, M.A.,Ardecky, R.J.,Zou, J.,Roosild, T.,Holmes, Z.J.,Nguyen, T.P.,Hedrick, M.P.,Rodiles, S.,Guan, A.,Grotegut, S.,Santelli, E.,Chung, T.D.Y.,Jackson, M.R.,Bottini, N.,Pinkerton, A.B.
Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase.
J.Med.Chem., 64:5645-5653, 2021

PubMed Abstract: Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.

PubMed: 33914534
DOI: 10.1021/acs.jmedchem.0c02126

実験手法

X-RAY DIFFRACTION (1.3 Å)