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Allosteric inhibition of protein tyrosine phosphatase 1B

Nature Structural & Molecular Biology volume 11, pages 730–737 (2004)Cite this article

Abstract

Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located ∼20 Å from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

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Figure 1: Noncompetitive inhibitors of PTP1B.
Figure 2: Crystal structures reveal a novel allosteric site in PTP1B.
Figure 3: Allosteric inhibitors bind the open conformation of PTP1B.
Figure 4: The closed, catalytically competent conformation and the allosteric-bound conformation are mutually exclusive.
Figure 5: Allosteric ligand prevents closure of the WPD loop.
Figure 6: Allosteric inhibitors show selectivity for PTP1B and stimulate the insulin signaling pathway in cells.
Figure 7: The allosteric-bound conformation is similar to conformations of PTP1B with the WPD loop in the open conformation.

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Acknowledgements

We thank S. Evarts and M. Cancilla for assistance with mass spectrometry; J. Smith for assistance with protein purification; S. Lam, T. Webb, and A. Shi for compound purification; J. Wells and E. Gordon for outstanding scientific consultations and enthusiastic support; and A. Weiss, J. Wells, B. Cunningham, M. Romanowski and T. O'Brien for critical reading of the manuscript. The work was supported in part by US National Institutes of Health small business innovation research grant R43-DK063764 to R.S.M and S.K.H.

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Author notes

  1. Christian Wiesmann

    Present address: Genentech, 1 DNA Way, South San Francisco, California, 94080, USA

  2. Christian Wiesmann, Kenneth J Barr and Jenny Kung: These authors contributed equally to this work.

Authors and Affiliations

  1. Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, 94080, California, USA

    Christian Wiesmann, Kenneth J Barr, Jenny Kung, Jiang Zhu, Daniel A Erlanson, Wang Shen, Bruce J Fahr, Min Zhong, Lisa Taylor, Mike Randal, Robert S McDowell & Stig K Hansen

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Supplementary information

Supplementary Video 1

Conformational changes between the closed conformation and the allosteric-inhibited conformation in the presence of compound 1. (MOV 3081 kb)

Tyr(P) (green) is shown in the active site in the closed conformation, but Tyr(P) dims as the conformation switches into the allosteric inhibited form. WPD loop and flanking residues are shown in purple, α3 in green, α6 in orange, and α7 in red. Trp291 on α7 is also shown. The structure in PDB entry 1PTY was used as a reference for the closed conformation. Created using the program PyMOL (DeLano Scientific, http://www.pymol.org).

Supplementary Methods (PDF 40 kb)

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Wiesmann, C., Barr, K., Kung, J. et al. Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 11, 730–737 (2004). https://doi.org/10.1038/nsmb803

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