Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 Å and the complex with tungstate

Stuckey, Jeanne A.; Schubert, Heidi; Fauman, Eric B.; Zhang, Zhong Yin; Dixon, Jack E.; Saper, Mark A.

doi:10.1038/370571a0

Cited by 414 publications

(492 citation statements)

References 26 publications

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“…The final models for the YopH•PVSN and YopH•PVS complexes included YopH residues 186-468 and all atoms in PVSN and PVS. The overall structure of YopH•PVSN is comparable to the previously determined ligand free YopH structure, 32 with root-mean-square derivation (RMSD) between all α-carbon positions of the two structures being 0.621 Å excluding the flexible WPD loop (residues 351-359). The major difference between these two structures is electron density in the PTP active site corresponding to PVSN, which is covalently attached to YopH via a thioether linkage between Cys403 Sγ and the terminal carbon of the vinyl group (Figure 4).…”

Section: Structural Basis Of Yoph Inactivation By Pvsn and Pvssupporting

confidence: 64%

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

et al. 2008

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Protein tyrosine phosphatases (PTPs) play key roles in the regulation of normal and pathological processes ranging from cell proliferation, differentiation, metabolism, and survival to many human diseases including cancer and diabetes. Functional studies of PTP can be greatly facilitated by small molecule probes that covalently label the active site of a PTP through an activity-dependent chemical reaction. In this communication, we characterize phenyl vinyl sulfonate (PVSN) and phenyl vinyl sulfone (PVS) as a new class of mechanism-based PTP probes. PVSN and PVS inactivate a broad range of PTPs in a time-and concentration-dependent fashion. The PVSN and PVS-mediated PTP inactivation is active site-directed and irreversible, resulting from a Michael addition of the active site Cys Sγ onto the terminal carbon of the vinyl group. Structural and mechanistic analyses reveal the molecular basis for the preference of PVSN/PVS toward the PTPs, which lies in the ability of PVSN and PVS to engage the conserved structural and catalytic machinery of the PTP active site. In contrast to early α-bromobenzyl phosphonate based probes, PVSN and PVS are resistant to solvolysis and are cell permeable, and thus hold promise for in vivo applications. Collectively, these properties bode well for the development of aryl vinyl sulfonates/sulfones based PTP probes to interrogate PTP activity in complex proteomes.

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Section: Structural Basis Of Yoph Inactivation By Pvsn and Pvssupporting

confidence: 64%

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

et al. 2008

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Section: Yophmentioning

confidence: 98%

“…1) (Black and Bliska, 1997;Persson et al, 1997;Black et al, 1998;Hamid et al, 1999). YopH bears a similar three-dimensional structure to the mammalian PTPases (Stuckey et al, 1994), suggesting that YopH most probably catalyses tyrosine phosphate hydrolysis via a similar mechanism to the mammalian PTPases.It is well established that tyrosine phosphorylation plays a role in respiratory burst induction (Yamaguchi et al, 1995). Therefore, it is not surprising that YopH down- Yersinia are translocated into the host cell via a type III secretion system.…”

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confidence: 98%

Yersinia effectors target mammalian signalling pathways

2002

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SummaryAnimals have an immune system to fight off challenges from both viruses and bacteria. The first line of defence is innate immunity, which is composed of cells that engulf pathogens as well as cells that release potent signalling molecules to activate an inflammatory response and the adaptive immune system. Pathogenic bacteria have evolved a set of weapons, or effectors, to ensure survival in the host. Yersinia spp. use a type III secretion system to translocate these effector proteins, called Yops, into the host. This report outlines how Yops thwart the signalling machinery of the host immune system. Introduction Innate immunity and signallingInnate immunity is the first line of defence against bacterial and viral infection (for a review of innate immunity, see Medzhitov and Janeway, 2000). The cells involved in the immune response use a wide variety of signalling cascades to activate processes such as phagocytosis, cytokine production and release and production of reactive oxygen species. In addition to eliminating pathogens, the innate immune system activates the adaptive immune response through the presentation of foreign peptides to T cells.Phagocytosis is an essential component of the innate immune system (May and Machesky, 2001). Rearrangement of the actin cytoskeleton during phagocytosis is mediated by the recruitment of proteins that function in actin rearrangement; these include paxillin, p130Cas and focal adhesion kinase (FAK) (Greenberg et al., 1990;Allen and Aderem, 1996). These proteins may form through M cells (microfold cells), which are specialized cells that take up foreign antigens, in intestinal Peyer's patches (Autenrieth and Firsching, 1996). Recognition of Yersinia by M cells is mediated via b1 integrins on the M-cell plasma membrane and the invasin protein of Yersinia (Marra and Isberg, 1997;Clark et al., 1998). Once Yersinia has penetrated the M cells, it can localize in the lymphoid tissue of its host.The recently sequenced genome of Y. pestis (Parkhill et al., 2001) suggests that many of the genes that Yersinia uses during infection and invasion, including adhesins, secretion systems and insecticidal toxins, have been acquired from other bacteria and viruses. Furthermore, all three pathogenic species of Yersinia harbour an extrachromosomal plasmid of 70 kb that is essential for virulence (Portnoy and Martinez, 1985). This plasmid contains the genes of a type III secretion system, a translocation apparatus highly conserved among pathogenic Gram-negative bacteria (for a review, see Cornelis, 1998). This secretion system is responsible for the translocation of the Yersinia effectors, termed Yops, into the host cell. Once inside the host cell, Yops carry out disruption of signalling cascades that activate the processes of phagocytosis, cytokine release and respiratory burst. Six Yop effectors have been identified (YopH, YopE, YopJ/P, YpkA/YopO, YopT and YopM). Some of these effectors are known to function in the downregulation of critical signalling cascades of the immune system (Fig...

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“…The crystal structure of the LMW-PTP has been recently determined [5]. Although this enzyme shows no general homology with respect to the main PTPase family members, it forms a three-dimensionally folded phosphate binding loop that is structurally identical to that contained in the human placenta PTPIB and Yersinia PTPases, both included in the main PTPase family [4,6].…”

Section: Introductionmentioning

confidence: 99%

PDGF receptor as a specific in vivo target for low M_r phosphotyrosine protein phosphatase

et al. 1995

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Low M r phosphotyrosine protein phosphatase (LMW-PTP) is a 18 kDa cytosolic enzyme widely distributed in eukaryotic cells. LMW-PTP catalyses the hydrolysis of phosphotyrosine residues and overexpression of the enzyme in normal and transformed cells inhibits cell proliferation. Site directed mutagenesis, together with crystallographic studies, have contributed to clarify the catalytic mechanism, which involves the active site signature sequence Ci2XXXXXRts , a main feature of all PTPase family members. In order to identify the LMW-PTP substrate/s we have expressed in NIH-3T3 cells a catalytically inert Cys 12 to Ser phosphatase mutant which has preserved its capacity for substrate binding. Overexpression of the mutant phosphatase leads to enhanced cell proliferation and serum induced mitogenesis, indicating that the mutation results in the production of a dominant negative protein. Analysis of mutant LMW-PTP expressing cells has enabled us to demonstrate an association between LMW-PTP and platelet derived growth factor receptor that appears to be highly specific. Our data suggest a catalytic action of LMW-PTP on the phosphorylated platelet derived growth factor receptor.

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Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 Å and the complex with tungstate

Cited by 414 publications

References 26 publications

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

Yersinia effectors target mammalian signalling pathways

PDGF receptor as a specific in vivo target for low M_r phosphotyrosine protein phosphatase

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Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 Å and the complex with tungstate

Cited by 414 publications

References 26 publications

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

Aryl Vinyl Sulfonates and Sulfones as Active Site-Directed and Mechanism-Based Probes for Protein Tyrosine Phosphatases

Yersinia effectors target mammalian signalling pathways

PDGF receptor as a specific in vivo target for low Mr phosphotyrosine protein phosphatase

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PDGF receptor as a specific in vivo target for low M_r phosphotyrosine protein phosphatase