title: Inhibition of Yersinia tyrosine phosphatase by furanyl salicylate compounds.
abstract: To avoid detection and targeting by the immune system, the plague-causing bacterium Yersinia pestis uses a type III secretion system to deliver a set of inhibitory proteins into the cytoplasm of immune cells. One of these proteins is an exceptionally active tyrosine phosphatase termed YopH, which paralyzes lymphocytes and macrophages by dephosphorylating critical tyrosine kinases and signal transduction molecules. Because Y. pestis strains lacking YopH are avirulent, we set out to develop small molecule inhibitors for YopH. We used a novel and cost-effective approach, in which leads from a chemical library screening were analyzed and computationally docked into the crystal structure of YopH. This resulted in the identification of a series of novel YopH inhibitors with nanomolar Ki values, as well as the structural basis for inhibition. Our inhibitors lack the polar phosphate-mimicking moiety of rationally designed tyrosine phosphatase inhibitors, and they readily entered live cells and rescued them from YopH-induced tyrosine dephosphorylation, signaling paralysis, and cell death. These inhibitors may become useful for treating the lethal infection by Y. pestis.
authors.affiliation: Infectious and Inflammatory Disease Center, The Burnham Institute, La Jolla, California 92037, USA.
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz
authors.forename: Shane
authors.initials: S
authors.lastname: Bruckner
authors.forename: Sina
authors.initials: S
authors.lastname: Sareth
authors.forename: Andres
authors.initials: A
authors.lastname: Alonso
authors.forename: Jori
authors.initials: J
authors.lastname: Bogetz
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D002151:Calorimetry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D010957:Plasmids; D011336:Probability; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000494:pharmacology*; D015010:Yersinia pestis / Q000201:enzymology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D012459:Salicylates; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia