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

Research output: Contribution to journalJournal articleResearchpeer-review

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.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume277
Issue number22
Pages (from-to)19982-19990
Number of pages10
ISSN0021-9258
DOIs
Publication statusPublished - 2002

Cite this

Iversen, L. F., Møller, K. B., Pedersen, A. K., Peters, G. H. J., Petersen, A. S., Andersen, H. S., ... Møller, N. P. H. (2002). Structure determination of T-cell protein-tyrosine phosphatase. Journal of Biological Chemistry, 277(22), 19982-19990. https://doi.org/10.1074/jbc.M200567200
Iversen, L.F. ; Møller, K. B. ; Pedersen, A.K. ; Peters, Günther H.J. ; Petersen, A.S. ; Andersen, H.S. ; Branner, S. ; Mortensen, S.B. ; Møller, N.P.H. / Structure determination of T-cell protein-tyrosine phosphatase. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 22. pp. 19982-19990.
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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.",
author = "L.F. Iversen and M{\o}ller, {K. B.} and A.K. Pedersen and Peters, {G{\"u}nther H.J.} and A.S. Petersen and H.S. Andersen and S. Branner and S.B. Mortensen and N.P.H. M{\o}ller",
year = "2002",
doi = "10.1074/jbc.M200567200",
language = "English",
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Iversen, LF, Møller, KB, Pedersen, AK, Peters, GHJ, Petersen, AS, Andersen, HS, Branner, S, Mortensen, SB & Møller, NPH 2002, 'Structure determination of T-cell protein-tyrosine phosphatase', Journal of Biological Chemistry, vol. 277, no. 22, pp. 19982-19990. https://doi.org/10.1074/jbc.M200567200

Structure determination of T-cell protein-tyrosine phosphatase. / Iversen, L.F.; Møller, K. B.; Pedersen, A.K.; Peters, Günther H.J.; Petersen, A.S.; Andersen, H.S.; Branner, S.; Mortensen, S.B.; Møller, N.P.H.

In: Journal of Biological Chemistry, Vol. 277, No. 22, 2002, p. 19982-19990.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Structure determination of T-cell protein-tyrosine phosphatase

AU - Iversen, L.F.

AU - Møller, K. B.

AU - Pedersen, A.K.

AU - Peters, Günther H.J.

AU - Petersen, A.S.

AU - Andersen, H.S.

AU - Branner, S.

AU - Mortensen, S.B.

AU - Møller, N.P.H.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M200567200

DO - 10.1074/jbc.M200567200

M3 - Journal article

VL - 277

SP - 19982

EP - 19990

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 22

ER -

Iversen LF, Møller KB, Pedersen AK, Peters GHJ, Petersen AS, Andersen HS et al. Structure determination of T-cell protein-tyrosine phosphatase. Journal of Biological Chemistry. 2002;277(22):19982-19990. https://doi.org/10.1074/jbc.M200567200