title: Isothiazolidinone (IZD) as a phosphoryl mimetic in inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH.
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.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute at Frederick, MD 21702-1201, USA.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Medhanit
authors.initials: M
authors.lastname: Bahta
authors.forename: George T
authors.initials: GT
authors.lastname: Lountos
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: David S
authors.initials: DS
authors.lastname: Waugh
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015010:Yersinia pestis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C512915:isothiazolidinone; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia