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  1. Article: Rationally designed peptide regulators of protein kinase C.

    Churchill, Eric N / Qvit, Nir / Mochly-Rosen, Daria

    Trends in endocrinology and metabolism: TEM

    2008  Volume 20, Issue 1, Page(s) 25–33

    Abstract: Protein-protein interactions sequester enzymes close to their substrates. Protein kinase C (PKC) is ... Short peptides derived from interaction sites between each PKC isozyme and its receptor for activated C ... kinase act as highly specific inhibitors and have become available as selective drugs in basic research ...

    Abstract Protein-protein interactions sequester enzymes close to their substrates. Protein kinase C (PKC) is one example of a ubiquitous signaling molecule with effects that are dependent upon localization. Short peptides derived from interaction sites between each PKC isozyme and its receptor for activated C kinase act as highly specific inhibitors and have become available as selective drugs in basic research and animal models of human diseases, such as myocardial infarction and hyperglycemia. Whereas the earlier inhibitory peptides are highly specific, we believe that peptides targeting additional interactions between PKC and selective substrates will generate even more selective tools that regulate different functions of individual isozymes. Here, we discuss the methodologies and applications for identifying selective regulators of PKC.
    MeSH term(s) Amino Acid Sequence ; Animals ; Drug Design ; Enzyme Activation/drug effects ; Enzyme Activators/chemical synthesis ; Enzyme Activators/chemistry ; Enzyme Activators/pharmacology ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Peptide Fragments/chemical synthesis ; Peptide Fragments/chemistry ; Peptide Fragments/pharmacology ; Protein Binding/drug effects ; Protein Kinase C/metabolism ; Protein Kinase C/physiology
    Chemical Substances Enzyme Activators ; Enzyme Inhibitors ; Peptide Fragments ; Protein Kinase C (EC 2.7.11.13)
    Language English
    Publishing date 2008-12-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1042384-9
    ISSN 1879-3061 ; 1043-2760
    ISSN (online) 1879-3061
    ISSN 1043-2760
    DOI 10.1016/j.tem.2008.10.002
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  2. Article ; Online: Delineating the role of c-FLIP/NEMO interaction in the CD95 network via rational design of molecular probes.

    Ivanisenko, Nikita V / Buchbinder, Jörn H / Espe, Johannes / Richter, Max / Bollmann, Miriam / Hillert, Laura K / Ivanisenko, Vladimir A / Lavrik, Inna N

    BMC genomics

    2019  Volume 20, Issue Suppl 3, Page(s) 293

    Abstract: ... rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure ... In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP ... the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and ...

    Abstract Background: Structural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mechanisms of CD95-mediated NF-κB activation and the role of c-FLIP/NEMO interaction in the induction of this pathway.
    Results: To this end, we have created the homology model of the c-FLIP/NEMO complex using the reported structure of the v-FLIP/NEMO complex, and rationally designed peptides targeting this complex. The designed peptides were based on the NEMO structure. Strikingly, the experimental in vitro validation demonstrated that the best inhibitory effects on CD95-mediated NF-κB activation are exhibited by the NEMO-derived peptides with the substitution D242Y of NEMO. Furthermore, we have assumed that the c-FLIP/NEMO complex is recruited to the DED filaments formed upon CD95 activation and validated this assumption in silico. Further insight into the function of c-FLIP/NEMO complex was provided by the analysis of evolutionary conservation of interacting regions which demonstrated that this interaction is common in distinct mammalian species.
    Conclusions: Taken together, using a combination of bioinformatics and experimental approaches we obtained new insights into CD95-mediated NF-κB activation, providing manifold possibilities for targeting the death receptor network.
    MeSH term(s) Amino Acid Sequence ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Computational Biology ; Humans ; I-kappa B Kinase/metabolism ; Molecular Probes ; NF-kappa B/metabolism ; Protein Interaction Domains and Motifs ; Protein Structure, Quaternary ; Sequence Alignment ; Signal Transduction ; fas Receptor/metabolism
    Chemical Substances CASP8 and FADD-Like Apoptosis Regulating Protein ; IKBKG protein, human ; Molecular Probes ; NF-kappa B ; fas Receptor ; I-kappa B Kinase (EC 2.7.11.10)
    Language English
    Publishing date 2019-05-08
    Publishing country England
    Document type Journal Article
    ISSN 1471-2164
    ISSN (online) 1471-2164
    DOI 10.1186/s12864-019-5539-y
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  3. Article ; Online: Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes.

    Pena, Darlene Aparecida / Andrade, Victor Piana de / Silva, Gabriela Ávila Fernandes / Neves, José Ivanildo / Oliveira, Paulo Sergio Lopes de / Alves, Maria Julia Manso / Devi, Lakshmi A / Schechtman, Deborah

    Scientific reports

    2016  Volume 6, Page(s) 22114

    Abstract: Protein kinase C (PKC) plays a regulatory role in key pathways in cancer ... used to select a peptide to generate an antibody that distinguishes active from inactive cPKC ... A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure ...

    Abstract Protein kinase C (PKC) plays a regulatory role in key pathways in cancer. However, since phosphorylation is a step for classical PKC (cPKC) maturation and does not correlate with activation, there is a lack of tools to detect active PKC in tissue samples. Here, a structure-based rational approach was used to select a peptide to generate an antibody that distinguishes active from inactive cPKC. A peptide conserved in all cPKCs, C2Cat, was chosen since modeling studies based on a crystal structure of PKCβ showed that it is localized at the interface between the C2 and catalytic domains of cPKCs in an inactive kinase. Anti-C2Cat recognizes active cPKCs at least two-fold better than inactive kinase in ELISA and immunoprecipitation assays, and detects the temporal dynamics of cPKC activation upon receptor or phorbol stimulation. Furthermore, the antibody is able to detect active PKC in human tissue. Higher levels of active cPKC were observed in the more aggressive triple negative breast cancer tumors as compared to the less aggressive estrogen receptor positive tumors. Thus, this antibody represents a reliable, hitherto unavailable and a valuable tool to study PKC activation in cells and tissues. Similar structure-based rational design strategies can be broadly applied to obtain active-state specific antibodies for other signal transduction molecules.
    MeSH term(s) Antibodies/metabolism ; Binding Sites/immunology ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Carcinogenesis ; Cell Line, Tumor ; Enzyme Activation ; Female ; Humans ; Isoenzymes/immunology ; Neoplasm Staging ; Neuroblastoma/immunology ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Peptide Fragments/immunology ; Protein Conformation ; Protein Domains/genetics ; Protein Kinase C beta/genetics ; Protein Kinase C beta/immunology ; Protein Kinase C beta/metabolism ; Receptors, Estrogen/metabolism ; Signal Transduction ; Structure-Activity Relationship
    Chemical Substances Antibodies ; Isoenzymes ; Peptide Fragments ; Receptors, Estrogen ; Protein Kinase C beta (EC 2.7.11.13)
    Language English
    Publishing date 2016-02-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep22114
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  4. Article ; Online: Rational Molecular Design of Potent PLK1 PBD Domain-binding Phosphopeptides Using Preferential Amino Acid Building Blocks.

    Mao, Xin-Li / Wang, Kui-Feng / Zhu, Feng / Pan, Zhao-Hu / Wu, Guo-Min / Zhu, Hong-Yuan

    Chemistry & biodiversity

    2016  Volume 13, Issue 8, Page(s) 1103–1110

    Abstract: ... proliferation. The protein has a highly conserved polo-box domain (PBD) present in C-terminal ... To practice computational findings, the profile was further employed to guide rational design of potent PBD ... as measured by a fluorescence anisotropy assay. The complex structure of PLK1 PBD domain with a newly designed ...

    Abstract Polo-like kinase 1 (PLK1) is an important regulator in diverse aspects of the cell cycle and proliferation. The protein has a highly conserved polo-box domain (PBD) present in C-terminal noncatalytic region, which exhibits a relatively broad sequence specificity in recognizing and binding phosphorylated substrates to control substrate phosphorylation by the kinase. In order to elucidate the structural basis, thermodynamic property, and biological implication underlying PBD-substrate recognition and association, a systematic amino acid preference profile of phosphopeptide interaction with PLK1 PBD domain was established via virtual mutagenesis analysis and mutation energy calculation, from which the contribution of different amino acids at each residue position of two reference phosphopeptides to domain-peptide binding was characterized comprehensively and quantitatively. With the profile, we are able to determine the favorable, neutral, and unfavorable amino acid types for each position of PBD-binding phosphopeptides, and we also explored the molecular origin of the broad sequence specificity in PBD-substrate recognition. To practice computational findings, the profile was further employed to guide rational design of potent PBD binders; three 6-mer phosphopeptides (i.e., IQSpSPC, LQSpTPF, and LNSpTPT) were successfully developed, which can efficiently target PBD domain with high affinity (Kd = 5.7 ± 1.1, 0.75 ± 0.18, and 7.2 ± 2.6 μm, resp.) as measured by a fluorescence anisotropy assay. The complex structure of PLK1 PBD domain with a newly designed, potent phosphopeptide LQSpTPF as well as diverse noncovalent chemical forces, such as H-bonds and hydrophobic interactions at the complex interface, were examined in detail to reveal the molecular mechanism of high affinity and stability of the complex system.
    MeSH term(s) Amino Acids/chemistry ; Amino Acids/metabolism ; Binding Sites ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Humans ; Models, Molecular ; Phosphopeptides/chemistry ; Phosphopeptides/metabolism ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/metabolism ; Thermodynamics ; Polo-Like Kinase 1
    Chemical Substances Amino Acids ; Cell Cycle Proteins ; Phosphopeptides ; Proto-Oncogene Proteins ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2016-08-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2139001-0
    ISSN 1612-1880 ; 1612-1872
    ISSN (online) 1612-1880
    ISSN 1612-1872
    DOI 10.1002/cbdv.201500513
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  5. Article ; Online: Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL.

    Kim, Sang-Woo / Rai, Deepak / McKeller, Morgan R / Aguiar, Ricardo C T

    Blood

    2009  Volume 113, Issue 24, Page(s) 6153–6160

    Abstract: ... of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role ... Identification of rational therapeutic targets is an important strategy to improve the cure rate ... These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K ...

    Abstract Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
    MeSH term(s) Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; Blotting, Western ; Cells, Cultured ; Cyclic AMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/genetics ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoblotting ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/genetics ; Lymphoma, Large B-Cell, Diffuse/enzymology ; Lymphoma, Large B-Cell, Diffuse/pathology ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphodiesterase 4 Inhibitors ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering/pharmacology ; Spleen/cytology ; Spleen/metabolism ; Syk Kinase
    Chemical Substances Enzyme Inhibitors ; Intracellular Signaling Peptides and Proteins ; Phosphodiesterase 4 Inhibitors ; RNA, Small Interfering ; Cyclic AMP (E0399OZS9N) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; PDE4B protein, human (EC 3.1.4.17)
    Language English
    Publishing date 2009-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2009-02-206128
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  6. Article: Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives.

    Ferreira, Carmen V / Justo, Giselle Z / Souza, Ana C S / Queiroz, Karla C S / Zambuzzi, William F / Aoyama, Hiroshi / Peppelenbosch, Maikel P

    Biochimie

    2006  Volume 88, Issue 12, Page(s) 1859–1873

    Abstract: ... events. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) have a pivotal role ... of both protein tyrosine kinases and PTPs is involved in the development of numerous congenitically inherited and acquired ... of phosphotyrosine mimetics into specific peptide templates (peptidomimetic backbones). Additional factors furthering ...

    Abstract Reversible phosphorylation of tyrosine residues is a key regulatory mechanism for numerous cellular events. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) have a pivotal role in regulating both normal cell physiology and pathophysiology. Accordingly, deregulated activity of both protein tyrosine kinases and PTPs is involved in the development of numerous congenitically inherited and acquired human diseases, prompting obvious pharmaceutical and academic research interest. The development of compound libraries with higher selective PTP inhibitory activity has been bolstered by the realization that many natural products have such activity and thus are interesting biologically lead compounds, which properties are widely exploited. In addition, more rational approaches have focused on the incorporation of phosphotyrosine mimetics into specific peptide templates (peptidomimetic backbones). Additional factors furthering discovery as well as therapeutic application of new bioactive molecules are the integration of functional genomics, cell biology, structural biology, drug design, molecular screening and chemical diversity. Together, all these factors will lead to new avenues to treat clinical disease based on PTP inhibition.
    MeSH term(s) Animals ; Biological Products/chemistry ; Biological Products/therapeutic use ; Drug Design ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/therapeutic use ; Humans ; Molecular Structure ; Protein Tyrosine Phosphatases/antagonists & inhibitors ; Protein Tyrosine Phosphatases/metabolism
    Chemical Substances Biological Products ; Enzyme Inhibitors ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2006-12
    Publishing country France
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 120345-9
    ISSN 0300-9084
    ISSN 0300-9084
    DOI 10.1016/j.biochi.2006.08.007
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