TY  - JOUR
A1  - Schulze, Jörg O.
A1  - Saladino, Giorgio
A1  - Busschots, Katrien
A1  - Neimanis, Sonja
A1  - Süß, Evelyn
A1  - Odadzic, Dalibor
A1  - Zeuzem, Stefan
A1  - Hindie, Valerie
A1  - Herbrand, Amanda K.
A1  - Lisa, María-Natalia
A1  - Alzari, Pedro M.
A1  - Gervasio, Francesco Luigi
A1  - Biondi, Ricardo M.
T1  - Bidirectional allosteric communication between the ATP-binding site and the regulatory PIF pocket in PDK1 protein kinase
T2  - Cell chemical biology
N2  - 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.
KW  - protein kinase
KW  - PDK1
KW  - Aurora
KW  - PIF pocket
KW  - allosteric regulation
KW  - small compounds
KW  - adenosine
KW  - GSK2334470
KW  - AGC kinase
KW  - molecular dynamics
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44387
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-443872
SN  - 2451-9456
N1  - Under an Elsevier user license
VL  - 23
IS  - 10
SP  - 1193
EP  - 1205
PB  - Elsevier
CY  - Amsterdam
ER  -