4C37: Pka-s6k1 Chimera With Compound 21a (cct196539) Bound

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.
PDB ID: 4C37Download
MMDB ID: 114360
PDB Deposition Date: 2013/8/21
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4C37: dimeric; determined by author and by software (PISA)
Molecular Components in 4C37
Label Count Molecule
Proteins (2 molecules)
Camp-dependent Protein Kinase Catalytic Subunit Alpha(Gene symbol: PRKACA)
Molecule annotation
Camp-dependent Protein Kinase Inhibitor Alpha(Gene symbol: PKIA)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB