China
Africa
Explore chapters and articles related to this topic
Development of an Oligodeoxynucleotide Pharmaceutical for the Treatment of Human Leukemia
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Alan M. Gewirtz, Deborah Lee Sokol
Recently, a putative leucine zipper structure was described within the amino terminal portion of Myb's carboxy terminal domain (Kanei-Ishii et al., 1992). Leucine zippers, such as those found in the transcription factors Jun, Fos, and Myc are thought to facilitate the protein-protein interactions which permit heterodimerization of DNA binding proteins. Such dimerization is thought to play a key role in regulating the transcriptional activity of these factors. A Myb dimerizing binding partner has yet to be identified but Myb-Myb homodimerization, which likely occurs through its leucine zipper, does lead to loss of DNA binding and transactivation ability (Nomura et al., 1993). Accordingly, one could reasonably postulate that Myb driven transactivation and/or transformation might be regulated by the binding of additional protein partners in the leucine zipper domain (Kanei-Ishii et al., 1992). Alternatively, loss of the ability of Myb to dimerize with a putative regulatory partner might also contribute, directly of indirectly, to cellular transformation and leukemogenesis. Point mutations in the Myb negative regulatory domain might be one mechanism for bringing about such a loss (Kanei-Ishii et al., 1992). Finally, interaction (not physical dimerization) with other nuclear binding proteins such as the CCAAT enhancer binding protein (C/BEP) (Burk et al., 1993), and the related myeloid nuclear factor NF-M (Ness et al., 1993) may also regulate Myb's transactivation or repressor functions.
Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CCAAT/enhancer binding protein (C/EBP), alpha gene (CEBPA) is a single exon gene located on chromosome 19q13.1 band. The gene belongs to a family of basic leucine zipper proteins, and encodes for a transcription factor that is crucial for maturation of hematopoietic myeloid cells; no mature granulocytes are observed in CEBPA-mutant mice and the t(8;21) translocation downregulates CEBPA to lead to AML [35–37]. The CEBPA gene has 2 transactivation domains at the N-terminus, and a basic region and leucine zipper region at the C-terminus. Mutations in CEBPA may be present in sporadic AML in 5%–14% cases. Most commonly, mutations in the N-terminus cause a frameshift, leading to premature termination and absence of the normal, full-length 42 kDa protein, but still allowing downstream expression for formation of the smaller 30 kDa protein, a dominant-negative isoform. Mutations in the C-terminus disrupt the leucine zipper region, which prevents dimerization and loss of DNA activity [36].
The Cell and Cell Division
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Following histone acetylation, various proteins bind to the promoter regions of genes to act as promoters and repressors. These can be classified into the following types: Helix-turn-helix proteins. These solely comprise amino acids and have a structure that facilitates binding into the major groove of DNA—their binding may block transcription or, conversely, may force bending of the DNA molecule facilitating transcription. The homeo-domain proteins are a type of helix-turn-helix protein involved in sequential embryonic development. Each of these homeo-domain proteins contains an identical section of 60 amino acids.Zinc finger proteins. Some transcription factors are rich in histidine and cysteine residues, which can bind zinc, thereby bending the protein into a finger-like shape. Steroid hormone receptors also contain several zinc fingers and are thought to function as transcription factors.Proteins with a leucine zipper motif. Certain a protein chains can form Y-shaped dimmers, which can attach to DNA; the two chains are held together by interactions between hydrophobic regions that are rich in leucine.Helix-loop-helix proteins. These form structures similar to leucine zippers.
SpyDisplay: A versatile phage display selection system using SpyTag/SpyCatcher technology
Published in mAbs, 2023
Sarah-Jane Kellmann, Christian Hentrich, Mateusz Putyrski, Hanh Hanuschka, Manuel Cavada, Achim Knappik, Francisco Ylera
Mazor et al. also achieved a separation of the expression of antibody and coat protein by forming a complex between an IgG and Fc-binding ZZ-domain-pIII fusion.30 Similarly, the Jun/Fos leucine zipper has been used to link the displayed protein to pIII.31 Since these methods are non-covalent, the complex might dissociate during stringent washing steps required for the selection of high-affinity antibodies. However, it is possible to stabilize the leucine zipper by introducing a disulfide bond between the dimerized proteins.32 CysDisplay is another phage display method to express the antibody separately from pIII and relies on the spontaneous formation of disulfide bonds between engineered free cysteines at the C-terminus of Fab heavy chain and the N-terminus of pIII. While this method has proven powerful and became the basis of the HuCAL platform,16 significant side reactions in this setup are the formation of pIII homodimers as well as Fab homodimers, making the control of the display rate much less straightforward compared to the specific SpyTag-SpyCatcher reaction.
Identifying dual leucine zipper kinase (DLK) inhibitors using e-pharamacophore screening and molecular docking
Published in Journal of Receptors and Signal Transduction, 2019
K. Langeswaran, Jeyakanthan Jeyaraman, Jegannath Babu R., Abir Biswas, K. R. Dhurgadevi
E-Pharmacophore generation is the synergistic approach on structure-based to obtain wide range of information. This method attempts to take a step beyond than simple contact scoring since it incorporates structural and energetic information using the scoring function in Glide XP. Seven-point pharmacophore sites were predicted. The hypothesis consists of a four H-bond acceptor (A), two aromatic ring(R) and one hydrophobic region (H) Figure 2. These predicted energetically favorable sites contain all the specific interactions of N-(1H-Pyrazol-3-yl) pyridin-2-aminer inhibitors with the Dual leucine zipper kinase protein. This information will be used to identify the new Dual leucine zipper kinase inhibitors. This predicted seven-point pharmacophore hypotheses is used as query to screening the new compounds from Maybridge, Chembridge, zinc, CNS, TCM, Life chemicals, and TOSLAB. The excluded volumes were added to the hypotheses to enrich further screening. Receptor-based excluded volumes were included in order to help reduce false positives by eliminating inactive compounds that cannot simultaneously match the hypothesis and avoid clashing with the receptor. Compounds with fitness scores of more than 2.0 were subjected to glide high-throughput virtual screening (HTVS).
Collective excitations in α-helical protein structures interacting with the water environment
Published in Electromagnetic Biology and Medicine, 2020
Vasiliy N. Kadantsev, Alexey Goltsov
Note, that the developed model of the α-helix interacting with its environment needs further development to build a more realistic model by considering tertiary interactions of α-helical structures in native proteins. As the α-helical structure is not stable in aqueous solution in the absence of tertiary interactions, our model in the current version can be directly applied to unfolded α-helical structures that are stable in solution. Such stable structures are the α-helical proteins and the α-helical Fs-peptide enriched with polar amino acid residues (e.g., alanine-rich peptides) which are stable in water environment due to shielding of backbone hydrogen bonds from water molecules (Ghosh et al. 2003). These α-helical structures interact with water molecules through only amino acid residues that were considered in our model (section 3). Moreover, α-helical structures form more complex ones stable in the solution such as the coiled-coil ones, supercoils (a superhelix) as well as α-helix barrel structures due to hydrophobic interaction of the non-polar side-chains (Lupas and Bassler 2017). The amphipathic α-helical coiled-coil structures play a significant role in molecular recognition and protein–protein interaction. For example, the leucine zipper (coiled-coil) structures are responsible for recognition and binding of the transcription factors with the DNA promoter regions of about short (~20) nucleotide sequence (Lupas and Bassler 2017). Excitation of the vibrational modes in the superhelices can be applied to explain the molecular recognition mechanism, long-range protein–protein (Fröhlich 1968a), and protein–DNA interaction (Kurian et al. 2018b), (Oldfield et al. 2005).