APOBEC3G, a member of the double-domain cytidine deaminase (CD) APOBEC, binds RNA to package into virions and restrict HIV-1 through deamination-dependent or deaminationindependent inhibition. Mainly due to lack of a full-length double-domain APOBEC structure, it is unknown how CD1/CD2 domains connect and how dimerization/multimerization is linked to RNA binding and virion packaging for HIV-1 restriction. We report rhesus macaque A3G structures that show different inter-domain packing through a short linker and refolding of CD2. The A3G dimer structure has a hydrophobic dimer-interface matching with that of the previously reported CD1 structure. A3G dimerization generates a surface with intensified positive electrostatic potentials (PEP) for RNA binding and dimer stabilization. Unexpectedly, mutating the PEP surface and the hydrophobic interface of A3G does not abolish virion packaging and HIV-1 restriction. The data support a model in which only one RNA-binding mode is critical for virion packaging and restriction of HIV-1 by A3G.
This mini-review summarized the current knowledge of inhibitors of interactions of beta-catenin/Tcf4 published to date according to their discovery approaches, and discussed their in vitro and in vivo activities, selectivities, and pharmacokinetic properties. Several reviews presently available now in this field describe modulators of the Wnt/beta-catenin pathway, but are generally focused on the bioactivities of these inhibitors. By contrast, this review focused on the drug discovery approaches taken in identifying these types of inhibitors and provided our perspective on further strategies for future drug discoveries. This review also integrated many recently published and important works on highly selective inhibitors as well as rational drug design. We believe that the findings and strategies summarized in this review have broad implications and will be of interest throughout the biochemical and pharmaceutical research community. AbstractThe Wnt/b-catenin signaling pathway typically shows aberrant activation in various cancer cells, especially colorectal cancer cells. This signaling pathway regulates the expression of a variety of tumor-related proteins, including c-myc and cyclin D1, and plays essential roles in tumorigenesis and in the development of many cancers. Small molecules that block the interactions between b-catenin and Tcf4, a downstream stage of activation of the Wnt/b-catenin signaling pathway, could efficiently cut off this signal transduction and thereby act as a novel class of anticancer drugs. This paper reviews the currently reported inhibitors that target b-catenin/Tcf4 interactions, focusing on the discovery approaches taken in the design of these inhibitors and their bioactivities. A brief perspective is then shared on the future discovery and development of this class of inhibitors. 1 In mammals, b-catenin is both structurally and functionally homologous to the product of the armadillo gene in Drosophila. b-Catenin plays a well-known role in cell-cell adhesion; 2 however, this protein is now receiving increasing attention from researchers in a variety of fields because of its essential role in the Wnt/ b-catenin signaling pathway. This signaling is involved in various developmental/maintenance processes in animals and shows a close relationship with tumorigenesis and the development of a wide range of cancers. 3-7The Wnt/b-catenin signaling pathway, also called the canonical Wnt signaling pathway, is quite ancient and evolutionarily conserved. Wnt signaling via b-catenin regulates many cell behaviors, such as proliferation, by shutting down b-catenin degradation, which causes b-catenin accumulation and subsequent activation of Tcf/Lef transcription factors. In the absence of the extracellular messenger Wnt, b-catenin undergoes degradation by forming a destruction complex consisting of adenomatous polyposis coli protein (APC), glycogen synthase kinase 3b (GSK3b), casein kinase 1a (CK1a), and Axin.8 CK1a and GSK3b phosphorylate b-catenin, making it recognizable by an E3 ubiquitin ligase,...
Overactivation or overexpression of β-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of β-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/β-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C(32)H(36)Cl(2)Cu(2)N(2)O(2)), which effectively inhibits the binding of β-catenin with Tcf4-derived peptide and suppresses β-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of β-catenin overexpressing HCT116 colon cancer cells that harbor the β-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down-regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/β-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets β-catenin/Tcf-4 interaction.
This work presents a convenient computation method to estimate whether a 4-substituted Hantzsch ester can be a good alkyl radical donor.
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