title: Allosteric inhibition of protein tyrosine phosphatase 1B.
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.
authors.affiliation: Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.forename: Jenny
authors.initials: J
authors.lastname: Kung
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Erlanson
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Fahr
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Lisa
authors.initials: L
authors.lastname: Taylor
authors.forename: Mike
authors.initials: M
authors.lastname: Randal
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Stig K
authors.initials: SK
authors.lastname: Hansen
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002384:Catalysis; D020134:Catalytic Domain; D003001:Cloning, Molecular; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009765:Obesity; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
chemical_list: D008024:Ligands; D014443:Tyrosine; D004247:DNA; D010744:Phosphoric Monoester Hydrolases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases