title: Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
abstract: PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe-Claire, Dorval, Quebec H9R 4P8, Canada. ernest_asanteappiah@merck.com
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.forename: Sangita
authors.initials: S
authors.lastname: Patel
authors.forename: Caroline
authors.initials: C
authors.lastname: Desponts
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Cheuk
authors.initials: C
authors.lastname: Lau
authors.forename: Claude
authors.initials: C
authors.lastname: Dufresne
authors.forename: Michel
authors.initials: M
authors.lastname: Therien
authors.forename: Rick
authors.initials: R
authors.lastname: Friesen
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Becker
authors.forename: Yves
authors.initials: Y
authors.lastname: Leblanc
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D014633:Valine / Q000737:chemistry
chemical_list: D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D004247:DNA; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D007930:Leucine; D014633:Valine