Journal article
Structure determination of T-cell protein-tyrosine phosphatase
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.
Language: | English |
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Year: | 2002 |
Pages: | 19982-19990 |
ISSN: | 1083351x , 00219258 and 10678816 |
Types: | Journal article |
DOI: | 10.1074/jbc.M200567200 |
ORCIDs: | Peters, Günther H.J. |
Amino Acid Motifs Amino Acid Sequence Animals Binding Sites Cloning, Molecular Crystallography, X-Ray Dimerization Hydrogen-Ion Concentration Kinetics Lysine Mice Models, Chemical Models, Molecular Molecular Sequence Data Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatase, Non-Receptor Type 2 Protein Tyrosine Phosphatases Ptpn1 protein, mouse Ptpn2 protein, mouse Sequence Homology, Amino Acid Structure-Activity Relationship Temperature