title: Structure determination of T cell protein-tyrosine phosphatase.
abstract: Protein-tyrosine phosphatase 1B (PTP1B) has recently received much attention as a potential drug target in type 2 diabetes. This has in particular been spurred by the finding that PTP1B knockout mice show increased insulin sensitivity and resistance to diet-induced obesity. Surprisingly, the highly homologous T cell protein-tyrosine phosphatase (TC-PTP) has received much less attention, and no x-ray structure has been provided. We have previously co-crystallized PTP1B with a number of low molecular weight inhibitors that inhibit TC-PTP with similar efficiency. Unexpectedly, we were not able to co-crystallize TC-PTP with the same set of inhibitors. This seems to be due to a multimerization process where residues 130-132, the DDQ loop, from one molecule is inserted into the active site of the neighboring molecule, resulting in a continuous string of interacting TC-PTP molecules. Importantly, despite the high degree of functional and structural similarity between TC-PTP and PTP1B, we have been able to identify areas close to the active site that might be addressed to develop selective inhibitors of each enzyme.
authors.affiliation: Protein Chemistry and Signal Transduction, Novo Nordisk, DK-2880 Bagsvaerd, Denmark. lfiv@novonordisk.com
authors.forename: Lars Fogh
authors.initials: LF
authors.lastname: Iversen
authors.forename: Karin Bach
authors.initials: KB
authors.lastname: Moller
authors.forename: Anja K
authors.initials: AK
authors.lastname: Pedersen
authors.forename: Gunther H
authors.initials: GH
authors.lastname: Peters
authors.forename: Annette S
authors.initials: AS
authors.lastname: Petersen
authors.forename: Henrik Sune
authors.initials: HS
authors.lastname: Andersen
authors.forename: Sven
authors.initials: S
authors.lastname: Branner
authors.forename: Steen B
authors.initials: SB
authors.lastname: Mortensen
authors.forename: Niels Peter Hundahl
authors.initials: NP
authors.lastname: Moller
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D019281:Dimerization; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C516653:Ptpn2 protein, mouse; D008239:Lysine