1. Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
- Author
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Evelyn Süß, Klaus Strebhardt, Isabelle Béquignon, Mourad Sanhaji, Larissa Pietsch, Birgit Caspar, Denis Kudlinzki, Harald Schwalbe, Krishna Saxena, Ricardo M. Biondi, Santosh Lakshmi Gande, Sridhar Sreeramulu, Monika Raab, and Amanda K. Herbrand
- Subjects
Phosphopeptides ,0301 basic medicine ,Allosteric regulation ,Enzyme Activators ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Spodoptera ,Biochemistry ,PLK1 ,allosteric inhibition ,Small Molecule Libraries ,purl.org/becyt/ford/1 [https] ,protein-protein interaction ,Ciencias Biológicas ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Catalytic Domain ,Proto-Oncogene Proteins ,Animals ,Humans ,Kinase activity ,Kinetochores ,purl.org/becyt/ford/1.6 [https] ,Protein Kinase Inhibitors ,Cell Proliferation ,Centrosome ,Kinase ,Chemistry ,small compounds ,General Medicine ,Bioquímica y Biología Molecular ,Cell biology ,Spindle apparatus ,G2 Phase Cell Cycle Checkpoints ,030104 developmental biology ,Protein kinase domain ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular Medicine ,Oligopeptides ,Multipolar spindles ,CIENCIAS NATURALES Y EXACTAS ,HeLa Cells ,Protein kinase regulation - Abstract
The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells. Fil: Raab, Monika. Goethe Universitat Frankfurt; Alemania Fil: Sanhaji, Mourad. Goethe Universitat Frankfurt; Alemania Fil: Pietsch, Larissa. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania Fil: Béquignon, Isabelle. Goethe Universitat Frankfurt; Alemania Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania Fil: Gande, Santosh L.. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania Fil: Caspar, Birgit. Goethe Universitat Frankfurt; Alemania Fil: Kudlinzki, Denis. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania Fil: Saxena, Krishna. Goethe Universitat Frankfurt; Alemania Fil: Sreeramulu, Sridhar. Goethe Universitat Frankfurt; Alemania Fil: Schwalbe, Harald. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania Fil: Strebhardt, Klaus. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania Fil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
- Published
- 2018
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