PDB 4CT1 deposited: 2014-03-11 modified: 2014-07-02
Title Human PDK1-PKCzeta Kinase Chimera in Complex with Allosteric Compound PS315 Bound to the PIF-Pocket
Authors Amon, S., Arencibia, J.M., Bauer, A.F., Biondi, R.M., Busschots, K., Engel, M., Jorgensen, T.J., Lopez-Garcia, L.A., Neimanis, S., Proschak, E., Schulze, J.O., Stark, H., Stroba, A., Zeuzem, S., Zhang, H.
Structure factors resolution 1.85 rfactor 0.1699 rfree 0.2155
DPI 0.33 theoretical min: 0.14
Related PDB Entries 4CT2

Protein kinases play important regulatory roles in cells and organisms. Therefore, they are subject to specific and tight mechanisms of regulation that ultimately converge on the catalytic domain and allow the kinases to be activated or inhibited only upon the appropriate stimuli. AGC protein kinases have a pocket in the catalytic domain, the PDK1-interacting fragment (PIF)-pocket, which is a key mediator of the activation. We show here that helix αC within the PIF-pocket of atypical protein kinase C (aPKC) is the target of the interaction with its inhibitory N-terminal domains. We also provide structural evidence that the small compound PS315 is an allosteric inhibitor that binds to the PIF-pocket of aPKC. PS315 exploits the physiological dynamics of helix αC for its binding and allosteric inhibition. The results will support research on allosteric mechanisms and selective drug development efforts against PKC isoforms.

Chem.Biol. 2014 Jun; 21(6):754- doi:10.1016/J.CHEMBIOL.2014.04.007

Cross References
Database source Identifier Description
PubMed 24836908 CBOLE2
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4CT1/0 4CT1 0 monomer 0 1 4 2270