Bidirectional allosteric communication between the ATP-binding site and the regulatory PIF pocket in PDK1 protein kinase

  • 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.
Metadaten
Author:Jörg O. Schulze, Giorgio Saladino, Katrien Busschots, Sonja Neimanis, Evelyn Süß, Dalibor Odadzic, Stefan ZeuzemORCiDGND, Valerie Hindie, Amanda K. Herbrand, María-Natalia Lisa, Pedro M. AlzariORCiD, Francesco Luigi Gervasio, Ricardo M. BiondiORCiDGND
URN:urn:nbn:de:hebis:30:3-443872
DOI:https://doi.org/10.1016/j.chembiol.2016.06.017
ISSN:2451-9456
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27693059
Parent Title (English):Cell chemical biology
Publisher:Elsevier
Place of publication:Amsterdam
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/09/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/11/28
Tag:AGC kinase; Aurora; GSK2334470; PDK1; PIF pocket; adenosine; allosteric regulation; molecular dynamics; protein kinase; small compounds
Volume:23
Issue:10
Page Number:14
First Page:1193
Last Page:1205
Note:
Under an Elsevier user license
HeBIS-PPN:427891752
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoDeutsches Urheberrecht