Structural basis for the dephosphorylating activity of PTPRQ towards phosphatidylinositide substrates.

Unlike other classical protein tyrosine phosphatases (PTPs), PTPRQ (PTP receptor type Q) has dephosphorylating activity towards phosphatidylinositide (PI) substrates. Here, the structure of the catalytic domain of PTPRQ was solved at 1.56 Å resolution.

Crystal structure of xenotropic murine leukaemia virus-related virus (XMRV) ribonuclease H.

RNase H (retroviral ribonuclease H) cleaves the phosphate backbone of the RNA template within an RNA/DNA hybrid to complete the synthesis of double-stranded viral DNA. In the present study we have determined the complete structure of the RNase H domain from XMRV (xenotropic murine leukaemia virus-related virus) RT (reverse transcriptase). The basic protrusion motif of the XMRV RNase H domain is folded as a short helix and an adjacent highly bent loop.

Identification of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as inhibitors of the phosphatase SerB653 in Porphyromonas gingivalis, implicated in periodontitis.

The serine phosphatase SerB653 plays a crucial role in the infection of Porphyromonas gingivalis, which contributes to the pathogenesis of periodontitis, an inflammatory disease of teeth-supporting tissues. Because functional loss of SerB653 eliminates the virulence of P. gingivalis, SerB653 inhibitors are considered potential periodontitis therapeutic or preventive agents.

Structure-based virtual screening approach to the discovery of novel inhibitors of eyes absent 2 phosphatase with various metal chelating moieties.

Despite a series of persuasive experimental evidence for the involvement of eyes absent protein tyrosine phosphatases in various human cancers, no small-molecule inhibitor has been reported so far. We have identified seven novel inhibitors of eyes absent homologue 2 (Eya2) with IC(50) values ranging from 1 to 70 μm by the virtual screening with docking simulations and enzyme inhibition assay. Atomic charges of the active-site Mg(2+) ion complex are calculated to enhance the accuracy of docking simulations.

Exploring binding sites other than the catalytic core in the crystal structure of the catalytic domain of MKP-4.

Map kinase phosphatase 4 (MKP-4), which has been implicated in signalling pathways that negatively regulate glucose uptake, belongs to the dual-specificity phosphatase (DUSP) family. An inherent property of MKPs is an ability to undergo structural rearrangement, transitioning from a partially active to a fully active conformation. Here, a 2.

Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor.

Eya proteins are transcription factors that play pivotal roles in organ formation during development by mediating interactions between Sine Oculis (SO) and Dachshund (DAC). Remarkably, the transcriptional activity of Eya proteins is regulated by a dephosphorylating activity within its Eya domain (ED). However, the molecular basis for the link between catalytic and transcriptional activities remains unclear.

Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent.

In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.

Discovery of novel Cdc25 phosphatase inhibitors with micromolar activity based on the structure-based virtual screening.

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy because of the correlation of their overexpression with a wide variety of cancers. We have been able to identify five novel Cdc25 phosphatase inhibitors with micromolar activity by means of a computer-aided drug design protocol involving the homology modeling of Cdc25A and the virtual screening with the automated AutoDock program implementing the effects of ligand solvation in the scoring function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC 50 values lower than 10 microM, they can be considered for further development by structure-activity relationship studies or de novo design methods.

Structure of human alpha-enolase (hENO1), a multifunctional glycolytic enzyme.

Aside from its enzymatic function in the glycolytic pathway, alpha-enolase (ENO1) has been implicated in numerous diseases, including metastatic cancer, autoimmune disorders, ischaemia and bacterial infection. The disease-related roles of ENO1 are mostly attributed to its immunogenic capacity, DNA-binding ability and plasmin(ogen) receptor function, which are significantly affected by its three-dimensional structure and surface properties, rather than its enzymatic activity. Here, the crystal structure of human ENO1 (hENO1) is presented at 2.

Discovery of novel PRL-3 inhibitors based on the structure-based virtual screening.

The inhibitors of phosphatase of regenerating liver-3 (PRL-3) have been shown to be useful as therapeutics for the treatment of cancer. We have been able to identify 12 novel PRL-3 inhibitors by means of the virtual screening with docking simulations under the consideration of the effects of ligand solvation in the scoring function. Because the newly identified inhibitors are structurally diverse and reveal a significant potency with IC(50) values ranging from 10 to 50muM, all of them can be considered for further development by structure-activity relationship or de novo design methods.

Structural basis for the cold adaptation of psychrophilic M37 lipase from Photobacterium lipolyticum.

The M37 lipase from Photobacterium lipolyticum shows an extremely low activation energy and strong activity at low temperatures, with optimum activity seen at 298 K and more than 75% of the optimum activity retained down to 278 K. Though the M37 lipase is most closely related to the filamentous fungal lipase, Rhizomucor miehei lipase (RML) at the primary structure level, their activity characteristics are completely different. In an effort to identify structural components of cold adaptation in lipases, we determined the crystal structure of the M37 lipase at 2.

Crystal structure of the catalytic domain of human MAP kinase phosphatase 5: structural insight into constitutively active phosphatase.

MAP kinase phosphatase 5 (MKP5) is a member of the mitogen-activated protein kinase phosphatase (MKP) family and selectively dephosphorylates JNK and p38. We have determined the crystal structure of the catalytic domain of human MKP5 (MKP5-C) to 1.6 A.

Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors.

A series of rhodanine derivatives was synthesized and evaluated for their ability to inhibit PRL-3. Benzylidene rhodanine derivative showed good biological activity, while compound 5e was the most active in this series exhibiting an IC50 value of 0.9 microM in vitro and showed a reduced invasion in cell-based assay.