1. Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
- Author
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Ricardo M. Biondi, Sonja Neimanis, Katrien Busschots, Pedro M. Alzari, Jörg O. Schulze, Evelyn Süß, Giorgio Saladino, Dalibor Odadzic, María-Natalia Lisa, Francesco Luigi Gervasio, Stefan Zeuzem, V. Hindie, Amanda K. Herbrand, Universitätsklinikum Frankfurt, University College of London [London] (UCL), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), The work was supported by BMBF GO-Bio (0315102), DFG BI 1044/2-3 and DFG BI 1044/12-1 (to R.M.B.) and in part by the Engineering and Physical Sciences Research Council (grant no. EP/M013898/1)., and Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Clinical Biochemistry ,PIF pocket ,MESH: Allosteric Regulation ,Biochemistry ,MAP2K7 ,Adenosine Triphosphate ,0302 clinical medicine ,Aurora Kinases ,MESH: Adenosine Triphosphate ,Drug Discovery ,MESH: Protein Kinase Inhibitors ,MESH: Allosteric Site ,Aurora ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,protein kinase ,MESH: Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,MESH: Indazoles ,ADENOSINE ,Cell biology ,Molecular Docking Simulation ,ALLOSTERIC REGULATION ,PDK1 ,adenosine ,MESH: HEK293 Cells ,030220 oncology & carcinogenesis ,Molecular Medicine ,PIF POCKET ,CIENCIAS NATURALES Y EXACTAS ,Allosteric Site ,AURORA ,Indazoles ,PROTEIN KINASE ,Otras Ciencias Biológicas ,[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] ,Allosteric regulation ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Protein Serine-Threonine Kinases ,Biology ,MESH: Protein-Serine-Threonine Kinases ,Ciencias Biológicas ,MESH: Aurora Kinases ,03 medical and health sciences ,GSK2334470 ,MESH: Molecular Docking Simulation ,[CHIM.CRIS]Chemical Sciences/Cristallography ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,ddc:610 ,c-Raf ,Binding site ,Protein kinase A ,Protein Kinase Inhibitors ,Molecular Biology ,Pharmacology ,Binding Sites ,MESH: Humans ,small compounds ,Cyclin-dependent kinase 2 ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,AGC kinase ,SMALL COMPOUNDS ,allosteric regulation ,molecular dynamics ,HEK293 Cells ,Pyrimidines ,030104 developmental biology ,MESH: Binding Sites ,Allosteric enzyme ,MESH: Pyrimidines ,biology.protein ,AGC KINASE ,MOLECULAR DYNAMICS ,Cyclin-dependent kinase 9 ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] - Abstract
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins. Fil: Schulze, Jörg O.. Goethe Universitat Frankfurt; Alemania Fil: Saladino, Giorgio. University College London; Reino Unido Fil: Busschots, Katrien. Goethe Universitat Frankfurt; Alemania Fil: Neimanis, Sonja. Goethe Universitat Frankfurt; Alemania Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania Fil: Hindie, Valerie. Goethe Universitat Frankfurt; Alemania Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania Fil: Lisa, María Natalia. Instituto Pasteur; Francia. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alzari, Pedro M.. Instituto Pasteur; Francia Fil: Gervasio, Francesco L.. University College London; Reino Unido Fil: Biondi, Ricardo Miguel. 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. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
- Published
- 2016