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Isothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH

  1. Author:
    Kim, S. E.
    Bahta, M.
    Lountos, G. T.
    Ulrich, R. G.
    Burke, T. R.
    Waugh, D. S.

  2. Author Address

    [Kim, SE; Bahta, M; Burke, TR] NCI, Biol Chem Lab, Frederick, MD 21702 USA [Lountos, GT; Waugh, DS] NCI, Ctr Macromol Crystallog, Frederick, MD 21702 USA [Ulrich, RG] USA, Lab Mol Immunol, Med Res Inst Infect Dis, Frederick, MD 21702 USA;Burke, TR (reprint author), NCI, Biol Chem Lab, POB B, Frederick, MD 21702 USA;tburke@helix.nih.gov waughd@mail.nih.gov
    1. Year: 2011
    2. Date: Jul
  2. Journal: Acta Crystallographica Section D-Biological Crystallography
    1. 67
    2. Pages: 639-645
  4. Type of Article: Article
  5. ISSN: 0907-4449
  1. Abstract:

    Isothiazolidinone (IZD) heterocycles can act as effective components of protein tyrosine phosphatase (PTP) inhibitors by simultaneously replicating the binding interactions of both a phosphoryl group and a highly conserved water molecule, as exemplified by the structures of several PTP1B-inhibitor complexes. In the first unambiguous demonstration of IZD interactions with a PTP other than PTP1B, it is shown by X-ray crystallography that the IZD motif binds within the catalytic site of the Yersinia pestis PTP YopH by similarly displacing a highly conserved water molecule. It is also shown that IZD-based bidentate ligands can inhibit YopH in a nonpromiscuous fashion at low micromolar concentrations. Hence, the IZD moiety may represent a useful starting point for the development of YopH inhibitors.

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External Sources

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  2. DOI: 10.1107/s0907444911018610
  3. View record in Web of Science®
  4. WOS: 000292461200006

Library Notes

  1. Fiscal Year: FY2010-2011
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