1T48

Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

Summary for 1T48

• Entry DOI: 10.2210/pdb1t48/pdb
• Related: 1PTY 1T49 2HNP
• Descriptor: Protein-tyrosine phosphatase, non-receptor type 1, 3-(3,5-DIBROMO-4-HYDROXY-BENZOYL)-2-ETHYL-BENZOFURAN-6-SULFONIC ACID DIMETHYLAMIDE (3 entities in total)
• Functional Keywords: allosteric inhibition, protein tyrosine phosphatase 1b, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P18031
• Total number of polymer chains: 1
• Total formula weight: 35251.78

Authors

Wiesmann, C.,Barr, K.J.,Kung, J.,Zhu, J.,Shen, W.,Fahr, B.J.,Zhong, M.,Erlanson, D.A.,Taylor, L.,Randal, M.,McDowell, R.S.,Hansen, S.K. (deposition date: 2004-04-28, release date: 2004-07-20, Last modification date: 2023-08-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)