7KH8

Human LMPTP in complex with inhibitor

Summary for 7KH8

• Entry DOI: 10.2210/pdb7kh8/pdb
• Descriptor: Low molecular weight phosphotyrosine protein phosphatase, 3-[(2,6-dichlorophenyl)methyl]-8-(2-methylphenyl)-3H-purin-6-amine, NITRATE ION, ... (4 entities in total)
• Functional Keywords: protein tyrosine phosphatase, lmwptp, inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 36609.01

Authors

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. (deposition date: 2020-10-20, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.3 Å)