Structural genomics of protein phosphatases

Almo, Steven C.; Bonanno, J.B.; Sauder, J.M.; Emtage, Spencer; DiLorenzo, Teresa P.; Malashkevich, V.N.; Wasserman, Steven R.; Swaminathan, Subramanyam; Eswaramoorthy, S.; Agarwal, Rashmi; Kumaran, D.; Madegowda, Mahendra; Sugadev, R.; Patskovsky, Y.; Alvarado, J. Brian; Ramagopal, U.A.; Faber-Barata, Joana; Chance, Mark R.; Šali, Andrej; Fiser, András; Zhang, Zhong Yin; Lawrence, David S.; Burley, S.K.

doi:10.1007/s10969-007-9036-1

Cited by 152 publications

(128 citation statements)

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“…For example, without filtering, certain giant proteins such as Titin were found in our search presumably because of the abundance of ␤-strands in their structure. As another example, the two SIM-like motifs found in small CTD phosphatase 3 (supplemental Table S1) are buried inside the protein according to its crystal structure (PDB 2HHL) (39) and are, therefore, unlikely to be exposed for SUMO interaction unless the protein is unfolded. Above all, a SIM prediction is more meaningful when closely tied to careful experimental validation.…”

Section: Discussionmentioning

confidence: 99%

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

Sun

Hunter

2012

Journal of Biological Chemistry

111

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Background: Sumoylation is recognized by proteins with SUMO-interacting motifs. Results: SUMO-interacting motifs were identified through a computational string search and validated in SUMO binding assays. Conclusion: Arkadia, FLASH, C5orf25, and SOBP all contain clustered SIMs. Significance: These proteins contain distinct SUMO binding structures responsible for the recognition of diverse forms of sumoylation.

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Section: Discussionmentioning

confidence: 99%

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

Sun

Hunter

2012

Journal of Biological Chemistry

111

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“…This dearth of information about phosphatases may be due to a smaller relative number of identifiable phosphatases than of kinases in the Plasmodium genome (20,23). However, it is not uncommon for phosphatases to be fewer due to their nonspecific mechanism of targeting phosphorylated substrates (24).…”

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confidence: 99%

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

et al. 2013

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Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth, we isolated the attenuated parasite C9, which carried a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500. This gene encodes a protein structurally similar to a mitogen-activated protein kinase (MAPK) phosphatase, except for two notable characteristics that alter the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low-activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly lower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9, validating the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S-phase cell cycle progression in P. falciparum. Malaria caused by Plasmodium falciparum infection is the major type of severe malaria and results in hundreds of thousands of deaths each year and hundreds of millions of clinical illnesses (1, 2). Within the blood of infected individuals, asexual forms of the intraerythrocytic parasite grow rapidly through successive cycles of growth and proliferation. In each asexual generation, active entry into erythrocytes is followed by a growth phase culminating in dynamic release of erythrocyte-invading merozoites. The Plasmodium mitotic cycle is not fully understood and differs from the well-defined models established in yeast and mammalian cells (3). Observing the exact mitotic transitions during the cycle has been difficult due to variations in processes such as chromatid segregation, nuclear division, and spindle formation (4). However, this pattern of development has been observed in other members of the Apicomplexa, such as Toxoplasma gondii and Eimeria tenella, demonstrating the importance and conservation of this process across the phylum (5, 6).In eukaryotic systems, phosphorylation cascades are critical to cellular development and depend on the coordinated activity of kinases, which are in turn modulated by the activity of phosphatases. There is growing evidence that kinases are critical regulators of cell growth and development in Plasmodium species (7-9). Plasmodium kinases, for example, have been found to be involved with the initial invasion of host cells in addition to egress and differentiation (6, 10). Additional studies have identified kinases in phosphorylation cascades of the gametocyte-ookinete-oocyst transition in the mosquito midgut (11)(12)(13)(14)(15)(16)(17). In contrast, few studies have described the phosphatases involved in these processes, which would understandably function with kinases to coregul...

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“…Because of the lack of structural information on DUSP16, we performed homology modeling using the X-ray crystal structure of DUSP9 (PDB entry: 2HXP) [8] as the template to build the 3D structure of DUSP16 necessary for the structure-based virtual screening. The sequence alignment between the phosphatase domains of DUSP9 and DUSP16 was derived with version 2.1 of the ClustalW program, 13 using the BLOSUM matrices for scoring the alignments.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel DUSP16 Phosphatase Inhibitors through Virtual Screening with Homology Modeled Protein Structure

Park

Nam

et al. 2014

SLAS Discovery

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Recently, dual-specificity phosphatase 16 (DUSP16) emerged as a promising therapeutic target protein for the development of anti-atherosclerosis and anticancer medicines. The present study was undertaken to identify the novel inhibitors of DUSP16 based on the structure-based virtual screening. We have been able to find seven novel inhibitors of DUSP16 through the drug design protocol involving homology modeling of the target protein, docking simulations between DUSP16 and its putative inhibitors with the modified scoring function, and in vitro enzyme assay. These inhibitors revealed good potency, with IC 50 values ranging from 1 to 22 µM, and they were also screened computationally for having desirable physicochemical properties as drug candidates. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory activity against DUSP16. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of DUSP16 are addressed in detail.

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Structural genomics of protein phosphatases

Cited by 152 publications

References 100 publications

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search

Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum

Discovery of Novel DUSP16 Phosphatase Inhibitors through Virtual Screening with Homology Modeled Protein Structure

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