Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase

Authors
Schulze, Jörg O.; Saladino, Giorgio; Busschots, Katrien; Neimanis, Sonja; Süß, Evelyn; Odadzic, Dalibor; Zeuzem, Stefan; Hindie, Valerie; Herbrand, Amanda K.; Lisa, María Natalia; Alzari, Pedro M.; Gervasio, Francesco L.; Biondi, Ricardo Miguel
Publication Year
2016
Language
English
Format
article
Status
Published version
Description
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
Subject
ADENOSINE
AGC KINASE
ALLOSTERIC REGULATION
AURORA
GSK2334470
MOLECULAR DYNAMICS
PDK1
PIF POCKET
PROTEIN KINASE
SMALL COMPOUNDS
Otras Ciencias Biológicas
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/55476