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Family Birnaviridae
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Saugar et al. (2005) solved the fine mechanism of the molecular switch. The authors showed that the molecular basis of the conformational flexibility of the pVP2 precursor was an amphipatic α helix formed by the sequence GFKDIIRAIR. The VP2 containing this α helix was able to assemble into the T = 13 capsid only when expressed as a chimeric protein with an N-terminal His tag. An amphiphilic α helix, which acted as a conformational switch, was thus responsible for the inherent structural polymorphism of the VP2 protein. The His tag mimicked the VP3 C-terminal region closely and acted as a molecular triggering factor. Using electron cryomicroscopy difference imaging at 15 Å resolution, both polypeptide elements were detected on the capsid inner surface (Saugar et al. 2005). Figure 14.5 illustrates these unique findings.
Molecular Imaging of Viable Cancer Cells
Published in Shoogo Ueno, Bioimaging, 2020
The second major category is “activatable probes,” whose fluorescence is initially suppressed, but is turned on by a molecular switch at tumor sites, providing a cancer-specific signal with high sensitivity and high TBR (Figure 2.1b). In order to design activatable fluorescent probes, it is important to control the fluorescence emission, and various strategies have been used to quench the fluorescence of the fluorophores, including Förster resonance energy transfer (FRET), photoinduced electron transfer (PeT), intramolecular spirocyclization, and self-quenching. The molecular switch at tumor sites is important to induce rapid and specific activation of the fluorescence signal, and may be a tumor-specific receptor, an enzymatic activity, or other tumor-specific target. In the following section, we briefly review the fluorescence switching mechanisms and describe probes based on these mechanisms.
Collection and Expansion of Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Based on current experimental evidence, it is most likely that neural cell lines, rather than stem cells themselves will be most useful for therapeutic purposes. Immortality, in the absence of transformation, represents a valuable property of neural cell lines that make them an attractive therapeutic tool. From the biosafety perspective, any long-term cultured, ex vivo expanded NSC preparation may be seen as a potential source of transformed cells, and bearing some risk for tumor generation. Extensive validation tests will be needed to exclude these possibilities before use in human therapies. Molecular switches designed to regulate or silence transgenes and/or to eradicate the cells may also be needed.
The role of Gα protein signaling in the membrane estrogen receptor-mediated signaling
Published in Gynecological Endocrinology, 2021
Shuhui Zheng, Lin Wu, Chao Fan, Jingxia Lin, Yaxing Zhang, Tommaso Simoncini, Xiaodong Fu
There are 16 Gα genes in the human genome, encoding 23 known Gα proteins. According to the sequence similarity, these proteins can be divided into four categories: Gα (s/OLF), Gα(I1/I2/I3/O/T-rod/t-cone/gust/z), Gα (Q/11/14/16) and Gα (12/13) [13]. G-proteins can be regarded as molecular switches. They turn on the further signaling cascades respond to the GPCRs’ activation by extracellular stimuli. Various ligands can bind to GPCRs and active G-protein, such as photons, many hormones, and neurotransmitters. In addition, some non-GPCR proteins can also regulate G protein, such as Ric-8 protein, GPR-domain containing proteins, GBA-motif containing proteins, and RGS-domain-containing proteins. The switching function of G-proteins depends on the Gα’s ability to cycle between an inactive GDP-bound and an active GTP-bound state. Agonists binding to GPCRs promote the release of bound GDP from Gα [39]. Then the nucleotide-free Gα binds to GTP, leading to the dissociation of G βγ. The downstream signaling is initiated by both GTP-bound Gα and free Gβγ through interacting with downstream effectors.
Advances in distributed computing with modern drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Antonio Jesús Banegas-Luna, Baldomero Imbernón, Antonio Llanes Castro, Alfonso Pérez-Garrido, José Pedro Cerón-Carrasco, Sandra Gesing, Ivan Merelli, Daniele D’Agostino, Horacio Pérez-Sánchez
Ligand-based methods (e.g. QSAR, similarity searching, pharmacophore modeling and docking) represent worthwhile solutions in drug discovery. However, QSAR and similarity searching do not take into account knowledge about the binding site within the protein target and this can reduce the accuracy of the calculations. To overcome this issue, structure-based methods are the preferred choice when the 3D structure of the target is known, although they are usually computationally more expensive than ligand-based approaches. In such cases, it is studied how the activity of proteins may be altered when small ligands dock into the well-defined cavities of protein receptors. These ligands can act as molecular switches and control the activity of the protein. For proteins involved in a metabolic pathway related to a disease, artificial ligands can act as drugs [32]. As more metabolic pathways and their associated key proteins are identified, the search for artificial ligands has intensified as a method of improving the treatment of various diseases. The number of known protein structures continues to grow exponentially, a trend increasingly complemented by initiatives in structural genomics [33]. Molecular docking identifies the lead compounds that can bind to a target protein with high affinity [34]. This is achieved by calculating the optimum binding position for each molecule in a large database of potential targets using heuristics and then ranking the database with a scoring function according to the estimated affinity [35].
Identification of glia phenotype modulators based on select glial function regulatory signaling pathways
Published in Expert Opinion on Drug Discovery, 2018
Considering the increasing number of studies supporting the phenotype-specific roles of microglia in the different phases of neurodegeneration, a first potential therapeutic approach may be to either turn on the molecular switch of ‘alternative’ activation or turn off the switch of ‘classic’ activation. In fact, several putative GPMs acting either as activators or inhibitors of key molecular switches have been identified as potential therapeutic interventions. A recent analysis of drugs approved by the FDA between 1999 and 2008 reported that the phenotypic approach is more successful than target-based approaches for the development of small-molecule first-in-class drugs. The above study revealed that seven of the eight small-molecule drugs approved for CNS diseases were identified using phenotypic assays, implying that this approach is particularly effective for complex and challenging disease areas, such as neurodegenerative diseases [122,123]. Thus, the discovery and development of drugs for neurodegenerative diseases could benefit from the use of phenotypic assays. In fact, most of the putative GPMs discussed in this review have been identified using phenotypic assays. However, whether these putative GPMs directly engage their target molecules remains to be determined in subsequent target-based assays.