4C35

PKA-S6K1 Chimera with compound 1 (NU1085) bound

Summary for 4C35

• Entry DOI: 10.2210/pdb4c35/pdb
• Related: 4C33 4C34 4C36 4C37 4C38
• Descriptor: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA, CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA, 2-(4-hydroxyphenyl)-1H-benzimidazole-4-carboxamide, ... (5 entities in total)
• Functional Keywords: transferase-inhibitor complex, chimera, s6k1, transferase/inhibitor
• Biological source: BOS TAURUS (BOVINE); More
• Total number of polymer chains: 2
• Total formula weight: 43373.25

Authors

Couty, S.,Westwood, I.M.,Kalusa, A.,Cano, C.,Travers, J.,Boxall, K.,Chow, C.L.,Burns, S.,Schmitt, J.,Pickard, L.,Barillari, C.,McAndrew, P.C.,Clarke, P.A.,Linardopoulos, S.,Griffin, R.J.,Aherne, G.W.,Raynaud, F.I.,Workman, P.,Jones, K.,van Montfort, R.L.M. (deposition date: 2013-08-21, release date: 2013-10-09, Last modification date: 2023-12-20)

Primary citation

Couty, S.,Westwood, I.M.,Kalusa, A.,Cano, C.,Travers, J.,Boxall, K.,Chow, C.L.,Burns, S.,Schmitt, J.,Pickard, L.,Barillari, C.,McAndrew, P.C.,Clarke, P.A.,Linardopoulos, S.,Griffin, R.J.,Aherne, G.W.,Raynaud, F.I.,Workman, P.,Jones, K.,van Montfort, R.L.
The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.
Oncotarget, 4:1647-1661, 2013

PubMed Abstract: 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.

PubMed: 24072592
DOI: 10.18632/oncotarget.1255

Experimental method

X-RAY DIFFRACTION (2.19 Å)