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The two-spotted spider mite Tetranychus urticae Koch (Acari: Tetranychidae) is an extreme generalist pest that feeds on more than 1000 plant species, of which approximately 150 are important agronomic crops, including soybean. The control of T. urticae largely depends on the use of chemical acaricides. However, it has evolved resistance to most of the currently available acaricides. Therefore, searching for natural compounds able to inhibit mite-specific proteins is a hot topic in the fields of acaricide development and pest management. In this study, we aimed to identify T. urticae-specific proteins that could be used as targets to the development of new bioacaricides using a workflow of structural genomics and bioinformatic approaches. Therefore, we compared the genomes of T. urticae, Homo sapiens, Glycine max, and Apis mellifera to identify mite-specific proteins. From the comparison, 6,224 T. urticae-specific proteins were found, which were compared with sequences deposited in the Protein Data Bank. Only one T. urticae protein (tetur07g02040–intradiol ring-cleavage dioxygenase) was identified with an experimentally determined structure. This protein target was used to perform structure-based virtual screening in two databases of natural compounds (Supernatural and NuBBe), aiming to identify natural compounds that selectively bind to the active site of the target. The effectiveness of the most promising compound (sn00007964) was shown in vitro by dioxygenase inhibition and in vivo by mite toxicity experiments. We confirm that structural genomics and bioinformatic approaches (combined with in vitro and in vivo techniques) can be used to identify and validate new protein targets that can be used to fight T. urticae infestations through the development of new potential bioacaricides. [ABSTRACT FROM AUTHOR]

TGF-β signaling promotes migration, invasion, and distant colonization of cancer cells in advanced metastatic cancers. TGF-β signaling suppresses the anti-tumor immune response in a tumor microenvironment, allowing sustained tumor growth. TGF-β plays an important role in normal physiology; thus it is no surprise that the clinical development of effective and safe TGF-β inhibitors has been hampered due to their high toxicity. We discovered that increased expression of LY6K in cancer cells led to increased TGF-β signaling and that inhibition of LY6K could lead to reduced TGF-β signaling and reduced in vivo tumor growth. LY6K is a highly cancer-specific protein, and it is not expressed in normal organs except in the testes. Thus, LY6K is a valid target for developing therapeutic strategies to inhibit TGF-β signaling in cancer cells. We employed in vitro pull-down assays and molecular dynamics simulations to understand the structural determinants of the TGF-β receptor complex with LY6K. This combined approach allowed us to identify the critical residues and dynamics of the LY6K interaction with the TGF-β receptor complex. These data are critical in designing novel drugs for the inhibition of TGF-β in LY6K expressing cancer, induction of anti-tumor immune response, and inhibition of tumor growth and metastatic spread. [ABSTRACT FROM AUTHOR]

Electron-reservoirmetallopolymers in which these nanomaterialsare robust in at least two oxidation states are being actively investigatedin view of applications as stable electron-transfer reagents. Hereliving ring-opening metathesis polymerization (ROMP) and diblock copolymerizationof norbornene derivatives are conducted in which the cationic organoironcomplex [FeCp(η6-C6Me6)][PF6] (Cp = η5-C5H4R) iscovalently attached to the norbornene motif with a short trimethyleneamido linker or a longer linker containing also the triethylene glycol(TEG) unit. Solubility constraints involved with the shorter linkerrequire that the ROMP reaction be conducted in dimethylformamide (DMF),whereas the solubilizing longer linker conveniently allows carryingout the ROMP reaction in dichloromethane (DCM). Cyclic voltammetry(CV) of all these metallopolymers shows the full reversibility ofthe FeII→ FeIreduction wave at −1.35V vs decamethylferrocene, [FeCp*2], and the numbers ofmonomer units found using the Bard–Anson method by CV are closeto the monomer/catalyst ratio used in the ROMP reaction. [ABSTRACT FROM AUTHOR]

Lymphocyte antigen 6K (LY6K) is a small GPI-linked protein that is normally expressed in testes. Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including cancers of the breast, ovary, gastrointestinal tract, head and neck, brain, bladder, and lung. LY6K is required for ERK-AKT and TGF-β pathways in cancer cells and is required for in vivo tumor growth. In this report, we describe a novel role for LY6K in mitosis and cytokinesis through aurora B kinase and its substrate histone H3 signaling axis. Further, we describe the structural basis of the molecular interaction of small molecule NSC243928 with LY6K protein and the disruption of LY6K-aurora B signaling in cell cycle progression due to LY6K-NSC243928 interaction. Overall, disruption of LY6K function via NSC243928 led to failed cytokinesis, multinucleated cells, DNA damage, senescence, and apoptosis of cancer cells. LY6K is not required for vital organ function, thus inhibition of LY6K signaling is an ideal therapeutic approach for hard-to-treat cancers that lack targeted therapy such as triple-negative breast cancer. • Discovery of a unique function for LY6K in mitosis and cytokinesis via aurora B kinase signaling in cancer cells. • Structural underpinnings of the interaction between the inhibitor NSC243928 and the protein LY6K. • Mechanism of action of small molecule NSC243928 in LY6K signaling. • NSC243928 inhibits cell cycle, disrupts mitosis and cytokinesis resulting in DNA damage, senescence, and cancer cell death. [ABSTRACT FROM AUTHOR]