Structure determination of T-cell protein-tyrosine phosphatase

L.F. Iversen, K. B. Møller, A.K. Pedersen, Günther H.J. Peters, A.S. Petersen, H.S. Andersen, S. Branner, S.B. Mortensen, N.P.H. Møller

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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.
Original languageEnglish
JournalJournal of Biological Chemistry
Issue number22
Pages (from-to)19982-19990
Number of pages10
Publication statusPublished - 2002


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