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

Schulze, JO; Saladino, G; Busschots, K; Neimanis, S; Süß, E; Odadzic, D; Zeuzem, S; ... Biondi, RM; + view all (2016) Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase. Cell Chemical Biology , 23 (10) pp. 1193-1205. 10.1016/j.chembiol.2016.06.017. Green open access

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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.

Type: Article
Title: Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.chembiol.2016.06.017
Publisher version: http://doi.org/10.1016/j.chembiol.2016.06.017
Language: English
Additional information: © 2016 Elsevier Ltd. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: AGC kinase, Aurora, GSK2334470, PDK1, PIF pocket, adenosine, allosteric regulation, molecular dynamics, protein kinase, small compounds
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1521369
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