LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 6 of total 6

Search options

  1. Article ; Online: The catalytic role of INCENP in Aurora B activation and the kinetic mechanism of Aurora B/INCENP.

    Yang, Jingsong / Zappacosta, Francesca / Annan, Roland S / Nurse, Kelvin / Tummino, Peter J / Copeland, Robert A / Lai, Zhihong

    The Biochemical journal

    2009  Volume 417, Issue 1, Page(s) 355–360

    Abstract: Aurora kinases are a family of serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. AurB (Aurora B kinase) has shown a clear link to cancer and is being pursued as an attractive cancer target. Multiple small molecules ... ...

    Abstract Aurora kinases are a family of serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. AurB (Aurora B kinase) has shown a clear link to cancer and is being pursued as an attractive cancer target. Multiple small molecules targeting AurB have entered the clinic for the treatment of cancer. A protein cofactor, INCENP (inner centromere protein), regulates the cellular localization and activation of AurB. In the present study, we examined the effect of INCENP on the activation kinetics of AurB and also elucidated the kinetic mechanism of AurB-catalysed substrate phosphorylation. We have concluded that: (i) substoichoimetric concentrations of INCENP are sufficient for AurB autophosphorylation at the activation loop residue Thr(232), and hence INCENP plays a catalytic role in AurB autophosphorylation; (ii) AurB/INCENP-catalysed phosphorylation of a peptide substrate proceeds through a rapid equilibrium random Bi Bi kinetic mechanism; and (iii) INCENP has relatively minor effects on the specific activity of AurB using a peptide substrate when compared with its role in AurB autoactivation. These results indicate that the effects of INCENP, and probably accessory proteins in general, may differ when enzymes are acting on different downstream targets.
    MeSH term(s) Animals ; Aurora Kinase B ; Aurora Kinases ; Catalysis ; Cell Line ; Chromosomal Proteins, Non-Histone/metabolism ; Enzyme Activation ; Humans ; Kinetics ; Mitosis ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism
    Chemical Substances Chromosomal Proteins, Non-Histone ; INCENP protein, human ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1) ; Aurora Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2009-01-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20081365
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.110: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.

    Zhao, Baoguang / Smallwood, Angela / Yang, Jingsong / Koretke, Kristin / Nurse, Kelvin / Calamari, Amy / Kirkpatrick, Robert B / Lai, Zhihong

    Protein science : a publication of the Protein Society

    2008  Volume 17, Issue 10, Page(s) 1791–1797

    Abstract: VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In ... ...

    Abstract VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a pi-pi interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.
    MeSH term(s) Aurora Kinases ; Catalytic Domain ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Crystallography ; Crystallography, X-Ray ; Humans ; Microtubule-Associated Proteins/chemistry ; Microtubule-Associated Proteins/metabolism ; Nuclear Proteins/chemistry ; Nuclear Proteins/metabolism ; Piperazines/chemistry ; Piperazines/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism
    Chemical Substances Cell Cycle Proteins ; Microtubule-Associated Proteins ; Nuclear Proteins ; Piperazines ; Recombinant Proteins ; TPX2 protein, human ; tozasertib (234335M86K) ; Aurora Kinases (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2008-07-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1110/ps.036590.108
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 3407: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 1: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

    Ramanjulu, Joshi M / Pesiridis, G Scott / Yang, Jingsong / Concha, Nestor / Singhaus, Robert / Zhang, Shu-Yun / Tran, Jean-Luc / Moore, Patrick / Lehmann, Stephanie / Eberl, H Christian / Muelbaier, Marcel / Schneck, Jessica L / Clemens, Jim / Adam, Michael / Mehlmann, John / Romano, Joseph / Morales, Angel / Kang, James / Leister, Lara /
    Graybill, Todd L / Charnley, Adam K / Ye, Guosen / Nevins, Neysa / Behnia, Kamelia / Wolf, Amaya I / Kasparcova, Viera / Nurse, Kelvin / Wang, Liping / Puhl, Ana C / Li, Yue / Klein, Michael / Hopson, Christopher B / Guss, Jeffrey / Bantscheff, Marcus / Bergamini, Giovanna / Reilly, Michael A / Lian, Yiqian / Duffy, Kevin J / Adams, Jerry / Foley, Kevin P / Gough, Peter J / Marquis, Robert W / Smothers, James / Hoos, Axel / Bertin, John

    Nature

    2019  Volume 570, Issue 7761, Page(s) E53

    Abstract: Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Language English
    Publishing date 2019-05-29
    Publishing country England
    Document type Published Erratum
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-019-1265-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article: Binding of TPX2 to Aurora A alters substrate and inhibitor interactions.

    Anderson, Kelly / Yang, Jingsong / Koretke, Kristin / Nurse, Kelvin / Calamari, Amy / Kirkpatrick, Robert B / Patrick, Denis / Silva, Domingos / Tummino, Peter J / Copeland, Robert A / Lai, Zhihong

    Biochemistry

    2007  Volume 46, Issue 36, Page(s) 10287–10295

    Abstract: The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expression of AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast, colon, and ovarian. TPX2 is a binding partner and ... ...

    Abstract The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expression of AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast, colon, and ovarian. TPX2 is a binding partner and activator of AurA. A fragment of TPX2 (residues 1-43) has been shown to be sufficient for binding, kinase activation, and protection from dephosphorylation. We have shown that the addition of TPX2(1-43) increases the catalytic efficiency of AurA. While TPX2 binding has no effect on the turnover number of AurA and does not change the reaction mechanism (characterized here to be a rapid equilibrium random mechanism), it increases the binding affinity of both ATP and a peptide substrate. We have also demonstrated differences in the inhibitor structure-activity relationship (SAR) in the presence or absence of TPX2(1-43). To better understand the differential SAR, we carried out computer modeling studies to gain insight into the effect of TPX2 on the binding interactions between AurA and inhibitors. Our working hypothesis is that TPX2 binding decreases the size and accessibility of a hydrophobic pocket, adjacent to the ATP site, to inhibitors.
    MeSH term(s) Adenosine Diphosphate/pharmacology ; Alanine ; Amino Acid Sequence ; Aurora Kinases ; Catalysis/drug effects ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Kinetics ; Microtubule-Associated Proteins/chemistry ; Microtubule-Associated Proteins/metabolism ; Microtubule-Associated Proteins/pharmacology ; Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/chemistry ; Nuclear Proteins/metabolism ; Nuclear Proteins/pharmacology ; Phosphopeptides/chemistry ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/chemistry ; Protein-Serine-Threonine Kinases/metabolism ; Staurosporine/pharmacology ; Structure-Activity Relationship ; Substrate Specificity/drug effects ; Titrimetry
    Chemical Substances Cell Cycle Proteins ; Enzyme Inhibitors ; Microtubule-Associated Proteins ; Nuclear Proteins ; Phosphopeptides ; TPX2 protein, human ; Adenosine Diphosphate (61D2G4IYVH) ; Aurora Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Staurosporine (H88EPA0A3N) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2007-09-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi7011355
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: Design of amidobenzimidazole STING receptor agonists with systemic activity.

    Ramanjulu, Joshi M / Pesiridis, G Scott / Yang, Jingsong / Concha, Nestor / Singhaus, Robert / Zhang, Shu-Yun / Tran, Jean-Luc / Moore, Patrick / Lehmann, Stephanie / Eberl, H Christian / Muelbaier, Marcel / Schneck, Jessica L / Clemens, Jim / Adam, Michael / Mehlmann, John / Romano, Joseph / Morales, Angel / Kang, James / Leister, Lara /
    Graybill, Todd L / Charnley, Adam K / Ye, Guosen / Nevins, Neysa / Behnia, Kamelia / Wolf, Amaya I / Kasparcova, Viera / Nurse, Kelvin / Wang, Liping / Puhl, Ana C / Li, Yue / Klein, Michael / Hopson, Christopher B / Guss, Jeffrey / Bantscheff, Marcus / Bergamini, Giovanna / Reilly, Michael A / Lian, Yiqian / Duffy, Kevin J / Adams, Jerry / Foley, Kevin P / Gough, Peter J / Marquis, Robert W / Smothers, James / Hoos, Axel / Bertin, John

    Nature

    2018  Volume 564, Issue 7736, Page(s) 439–443

    Abstract: Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self ... ...

    Abstract Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA
    MeSH term(s) Animals ; Benzimidazoles/administration & dosage ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology ; Benzimidazoles/therapeutic use ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/immunology ; Drug Design ; Humans ; Ligands ; Membrane Proteins/agonists ; Membrane Proteins/immunology ; Mice ; Models, Molecular ; Nucleotides, Cyclic/metabolism
    Chemical Substances Benzimidazoles ; Ligands ; Membrane Proteins ; Nucleotides, Cyclic ; STING1 protein, human ; Sting1 protein, mouse ; cyclic guanosine monophosphate-adenosine monophosphate
    Language English
    Publishing date 2018-11-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-018-0705-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.

    Chan-Penebre, Elayne / Kuplast, Kristy G / Majer, Christina R / Boriack-Sjodin, P Ann / Wigle, Tim J / Johnston, L Danielle / Rioux, Nathalie / Munchhof, Michael J / Jin, Lei / Jacques, Suzanne L / West, Kip A / Lingaraj, Trupti / Stickland, Kimberly / Ribich, Scott A / Raimondi, Alejandra / Scott, Margaret Porter / Waters, Nigel J / Pollock, Roy M / Smith, Jesse J /
    Barbash, Olena / Pappalardi, Melissa / Ho, Thau F / Nurse, Kelvin / Oza, Khyati P / Gallagher, Kathleen T / Kruger, Ryan / Moyer, Mikel P / Copeland, Robert A / Chesworth, Richard / Duncan, Kenneth W

    Nature chemical biology

    2015  Volume 11, Issue 6, Page(s) 432–437

    Abstract: Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell ... ...

    Abstract Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Humans ; Inhibitory Concentration 50 ; Isoquinolines/chemistry ; Isoquinolines/pharmacology ; Isoquinolines/therapeutic use ; Lymphoma, Mantle-Cell/drug therapy ; Lymphoma, Mantle-Cell/enzymology ; Lymphoma, Mantle-Cell/pathology ; Male ; Methylation ; Mice, Inbred Strains ; Models, Molecular ; Molecular Structure ; Protein Binding ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Xenograft Model Antitumor Assays ; snRNP Core Proteins/metabolism
    Chemical Substances Antineoplastic Agents ; GSK3235025 ; Isoquinolines ; Pyrimidines ; SNRPD3 protein, human ; snRNP Core Proteins ; PRMT5 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319)
    Language English
    Publishing date 2015-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/nchembio.1810
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 90: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top