Yersinia pestis and Approaches to Targeting its Outer Protein H Protein-Tyrosine Phosphatase (YopH)

Bahta, Medhanit; Burke, Terrence R.

doi:10.2174/092986712803988866

Cited by 11 publications

(7 citation statements)

References 84 publications

(137 reference statements)

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“…The crystal structure of YopH indicates that its N- and C-terminal domains are linked by a proline-rich sequence. The N-terminal domain contains a type III secretion signal, a chaperon-binding region and a substrate-binding domain (Khandelwal et al, 2002), while the C-terminal domain includes a PTPase catalytic domain and an additional substrate-binding domain (Phan et al, 2003; Bahta and Burke, 2012). These two substrate recognition domains cooperate to reinforce binding of YopH to its substrate and enhance its activity and virulence.…”

Section: Antiphagocytic Factormentioning

confidence: 99%

Yersinia pestis: mechanisms of entry into and resistance to the host cell

Yuan

Chen

Yang

2013

Front. Cell. Infect. Microbiol.

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During infection, Yersinia, a facultative intracellular bacterial species, exhibits the ability to first invade host cells and then counteract phagocytosis by the host cells. During these two distinct stages, invasion or antiphagocytic factors assist bacteria in manipulating host cells to accomplish each of these functions; however, the mechanism through which Yersinia regulates these functions during each step remains unclear. Here, we discuss those factors that seem to function reversely and give some hypothesis about how bacteria switch between the two distinct status.

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Section: Antiphagocytic Factormentioning

confidence: 99%

Yersinia pestis: mechanisms of entry into and resistance to the host cell

Yuan

Chen

Yang

2013

Front. Cell. Infect. Microbiol.

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“…While drug-design efforts targeting PTKs have resulted in the development of many inhibitors that are used in the clinic today, medicinal chemistry efforts targeting PTPs lag far behind and remain very challenging. Nevertheless, several PTPs have the potential to serve as important drug targets for a variety of diseases such as cancer, diabetes, neurological and autoimmune disorders, inflammation and numerous pathogenic infections (Blaskovich, 2009;Bialy & Waldmann, 2005;Tautz et al, 2006;Alonso et al, 2004;Mustelin, 2006;Bahta & Burke, 2012;Guan & Dixon, 1993;Zhou et al, 2010;Bö hmer et al, 2013). PTPs are generally considered to be difficult targets for therapeutic intervention, in part because of their highly conserved active sites.…”

Section: Introductionmentioning

confidence: 99%

High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

Lountos

Raran-Kurussi

Zhao

et al. 2018

Acta Cryst Sect D Struct Biol

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Here, new crystal structures are presented of the isolated membrane‐proximal D1 and distal D2 domains of protein tyrosine phosphatase epsilon (PTPϵ), a protein tyrosine phosphatase that has been shown to play a positive role in the survival of human breast cancer cells. A triple mutant of the PTPϵ D2 domain (A455N/V457Y/E597D) was also constructed to reconstitute the residues of the PTPϵ D1 catalytic domain that are important for phosphatase activity, resulting in only a slight increase in the phosphatase activity compared with the native D2 protein. The structures reported here are of sufficient resolution for structure‐based drug design, and a microarray‐based assay for high‐throughput screening to identify small‐molecule inhibitors of the PTPϵ D1 domain is also described.

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“…Yersinia sp . utilizes a type III secretion system for translocation of virulence effectors into the host cell [ 3 ]. All three Yersinia species contain a 70kb plasmid that encodes a type III complex system and effectors (Yops).…”

Section: Introductionmentioning

confidence: 99%

Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor ofYersinia pestis

et al. 2015

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YopH is a bacterial protein tyrosine phosphatase, which is essential for the viability and pathogenic virulence of the plague-causing Yersinia sp. bacteria. Inactivation of YopH activity would lead to the loss of bacterial pathogenicity. We have studied the inhibitory properties of aurintricarboxylic acid (ATA) against YopH phosphatase and found that at nanomolar concentrations ATA reversibly decreases the activity of YopH. Computational docking studies indicated that in all binding poses ATA binds in the YopH active site. Molecular dynamics simulations showed that in the predicted binding pose, ATA binds to the essential Cys403 and Arg409 residues in the active site and has a stronger binding affinity than the natural substrate (pTyr). The cyclic voltammetry experiments suggest that ATA reacts remarkably strongly with molecular oxygen. Additionally, the electrochemical reduction of ATA in the presence of a negative potential from −2.0 to 2.5 V generates a current signal, which is observed for hydrogen peroxide. Here we showed that ATA indicates a unique mechanism of YopH inactivation due to a redox process. We proposed that the potent inhibitory properties of ATA are a result of its strong binding in the YopH active site and in situ generation of hydrogen peroxide near catalytic cysteine residue.

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Yersinia pestis and Approaches to Targeting its Outer Protein H Protein-Tyrosine Phosphatase (YopH)

Cited by 11 publications

References 84 publications

Yersinia pestis: mechanisms of entry into and resistance to the host cell

Yersinia pestis: mechanisms of entry into and resistance to the host cell

High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor ofYersinia pestis

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