Open AccessIsothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH
Author(s) -
Kim SungEun,
Bahta Medhanit,
Lountos George T.,
Ulrich Robert G.,
Burke Terrence R.,
Waugh David S.
Publication year - 2011
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444911018610
Subject(s) - yersinia pestis , protein tyrosine phosphatase , chemistry , phosphatase , biochemistry , stereochemistry , moiety , binding site , tyrosine , biology , enzyme , virulence , gene
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.