Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.
View Article and Find Full Text PDFThe tumor microenvironment (TME) has emerged as a valuable therapeutic target in glioblastoma (GBM), as it promotes tumorigenesis via an increased production of reactive oxygen species (ROS). Immune cells such as microglia accumulate near the tumor and its hypoxic core, fostering tumor proliferation and angiogenesis. In this study, we explored the therapeutic potential of natural polyphenols with antioxidant and anti-inflammatory properties.
View Article and Find Full Text PDFResistance to drought stress is fundamental to plant survival and development. Abscisic acid (ABA) is one of the major hormones involved in different types of abiotic and biotic stress responses. ABA intracellular signaling has been extensively explored in and occurs a phosphorylation cascade mediated by three related protein kinases, denominated SnRK2s (SNF1-related protein kinases).
View Article and Find Full Text PDFRagulator is a pentamer composed of p18, MP1, p14, C7orf59, and hepatitis B virus X-interacting protein (HBXIP; LAMTOR 1-5) which acts as a lysosomal scaffold of the Rag GTPases in the amino acid sensitive branch of TORC1 signaling. Here, we present the crystal structure of human HBXIP-C7orf59 dimer (LAMTOR 4/5) at 2.9 Å and identify a phosphorylation site on C7orf59 which modulates its interaction with p18.
View Article and Find Full Text PDFThe serine/arginine-rich protein kinase 2 (SRPK2) has been reported as upregulated in several cancer types, with roles in hallmarks such as cell migration, growth, and apoptosis. These findings have indicated that SRPK2 is a promising emerging target in drug discovery initiatives. Although high-resolution models are available for SRPK2 (PDB 2X7G), they have been obtained with a heavily truncated recombinant protein version (~50% of the primary structure), due to the presence of long intrinsically unstructured regions.
View Article and Find Full Text PDFMAF1 is the main RNA polymerase (Pol) III repressor that controls cell growth in eukaryotes. The Citrus ortholog, CsMAF1, was shown to restrict cell growth in citrus canker disease but its role in plant development and disease is still unclear. We solved the crystal structure of the globular core of CsMAF1, which reveals additional structural elements compared with the previously available structure of hMAF1, and explored the dynamics of its flexible regions not present in the structure.
View Article and Find Full Text PDFSugarcane is a unique crop with the ability to accumulate high levels of sugar and is a commercially viable source of biomass for bioelectricity and second-generation bioethanol. Water deficit is the single largest abiotic stress affecting sugarcane productivity and the development of water use efficient and drought tolerant cultivars is an imperative for all major sugarcane producing countries. This review summarizes the physiological and molecular studies on water deficit stress in sugarcane, with the aim to help formulate more effective research strategies for advancing our knowledge on genes and mechanisms underpinning plant response to water stress.
View Article and Find Full Text PDFTOR signaling pathway regulator-like (TIPRL) is a regulatory protein which inhibits the catalytic subunits of Type 2A phosphatases. Several cellular contexts have been proposed for TIPRL, such as regulation of mTOR signaling, inhibition of apoptosis and biogenesis and recycling of PP2A, however, the underlying molecular mechanism is still poorly understood. We have solved the crystal structure of human TIPRL at 2.
View Article and Find Full Text PDFBackground: Neks are serine-threonine kinases that are similar to NIMA, a protein found in Aspergillus nidulans which is essential for cell division. In humans there are eleven Neks which are involved in different biological functions besides the cell cycle control. Nek4 is one of the largest members of the Nek family and has been related to the primary cilia formation and in DNA damage response.
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