S-Trityl-L-cysteine Is a Reversible, Tight Binding Inhibitor of the Human Kinesin Eg5 That Specifically Blocks Mitotic Progression

Autor: Richard H. Wade, Luc Lebeau, Dimitrios A. Skoufias, Robert A. Cross, Yasmina Saoudi, Isabelle Crevel, Salvatore DeBonis, Frank Kozielski, David D. Hackney
Přispěvatelé: Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Marie Curie Research Institute, MRCI, Department of Biological Sciences [Pittsburgh], Carnegie Mellon University [Pittsburgh] (CMU), This work was supported by Contract 5197 from Association pour la Recherche sur le Cancer, Alliance Des Recherches sur le Cancer, and Contracts 03 013690 02 and 03 013690 01 from the Re´gion Rhoˆ ne-Alpes. The costs of publication of this article were defrayed in part by the payment of page charges., Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The Beatson Institute for Cancer Research, University of Glasgow, Andrieux, Annie
Rok vydání: 2006
Předmět:
MESH: Osteosarcoma
[SDV]Life Sciences [q-bio]
Kinesins
MESH: Drug Design
Biochemistry
MESH: Recombinant Proteins
MESH: Protein Structure
Tertiary
chemistry.chemical_compound
0302 clinical medicine
ortho-Aminobenzoates
MESH: Animals
ComputingMilieux_MISCELLANEOUS
Osteosarcoma
0303 health sciences
MESH: Anthranilic Acids
Stereoisomerism
Cell cycle
Microtubule sliding
MESH: Bone Neoplasms
Recombinant Proteins
Cell biology
Adenosine Diphosphate
MESH: Cattle
Monastrol
030220 oncology & carcinogenesis
MESH: Cell Division
Kinesin
Cell Division
Protein Binding
Mitosis
Bone Neoplasms
Spindle Apparatus
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
03 medical and health sciences
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
[CHIM]Chemical Sciences
Animals
Humans
MESH: Protein Binding
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Cysteine
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Molecular Biology
030304 developmental biology
MESH: Mitotic Spindle Apparatus
MESH: Humans
MESH: Adenosine Diphosphate
Cell Biology
MESH: Mitosis
MESH: Cysteine
MESH: Stereoisomerism
Protein Structure
Tertiary
Spindle apparatus
MESH: Hela Cells
chemistry
Centrosome
Cell culture
Drug Design
Cattle
MESH: Kinesin
HeLa Cells
Zdroj: Journal of Biological Chemistry
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (26), pp.17559-69. ⟨10.1074/jbc.M511735200⟩
Journal of Biological Chemistry, 2006, 281 (26), pp.17559-69. ⟨10.1074/jbc.M511735200⟩
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (26), pp.17559-17569. ⟨10.1074/jbc.M511735200⟩
Journal of Biological Chemistry, 2006, 281 (26), pp.17559-17569. ⟨10.1074/jbc.M511735200⟩
ISSN: 0021-9258
1083-351X
DOI: 10.1074/jbc.m511735200
Popis: International audience; Human Eg5, responsible for the formation of the bipolar mitotic spindle, has been identified recently as one of the targets of S-trityl-L-cysteine, a potent tumor growth inhibitor in the NCI 60 tumor cell line screen. Here we show that in cell-based assays S-trityl-L-cysteine does not prevent cell cycle progression at the S or G(2) phases but inhibits both separation of the duplicated centrosomes and bipolar spindle formation, thereby blocking cells specifically in the M phase of the cell cycle with monoastral spindles. Following removal of S-trityl-L-cysteine, mitotically arrested cells exit mitosis normally. In vitro, S-trityl-L-cysteine targets the catalytic domain of Eg5 and inhibits Eg5 basal and microtubule-activated ATPase activity as well as mant-ADP release. S-trityl-L-cysteine is a tight binding inhibitor (estimation of K(i,app)
Databáze: OpenAIRE
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