PDBsum entry 4c38

Transferase/inhibitor

PDB id: 4c38

Contents

Protein chains

337 a.a.

20 a.a.

Ligands

VUP

MOH ×3

Waters ×634

PDB id:

4c38

Name:

Transferase/inhibitor

Title:

Pka-s6k1 chimera with compound 21e (cct239066) bound

Structure:

Camp-dependent protein kinase catalytic subunit alpha. Chain: a. Synonym: pka c-alpha. Engineered: yes. Mutation: yes. Other_details: pka-s6k1 chimera. Camp-dependent protein kinase inhibitor peptide. Chain: i. Fragment: residues 5-24.

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 9913

Resolution:

1.58Å R-factor: 0.155 R-free: 0.178

Authors:

S.Couty,I.M.Westwood,A.Kalusa,C.Cano,J.Travers,K.Boxall,C.L.Chow, S.Burns,J.Schmitt,L.Pickard,C.Barillari,P.C.Mcandrew,P.A.Clarke, S.Linardopoulos,R.J.Griffin,G.W.Aherne,F.I.Raynaud,P.Workman, K.Jones,R.L.M.Van Montfort

Key ref:

S.Couty et al. (2013). The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. Oncotarget, 4, 1647-1661. PubMed id: 24072592 DOI: 10.18632/oncotarget.1255

Date:

21-Aug-13 Release date: 09-Oct-13

Protein chain

P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus

Seq: 351 a.a.

Struc: 337 a.a.*

Protein chain

Q3SX13  (IPKA_BOVIN) -  cAMP-dependent protein kinase inhibitor alpha from Bos taurus

Seq: 76 a.a.

Struc: 20 a.a.

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.11.11 - cAMP-dependent protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = VUP) matches with 45.16% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = VUP) matches with 45.16% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.18632/oncotarget.1255

Oncotarget 4:1647-1661 (2013)

PubMed id: 24072592

The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.

S.Couty, I.M.Westwood, A.Kalusa, C.Cano, J.Travers, K.Boxall, C.L.Chow, S.Burns, J.Schmitt, L.Pickard, C.Barillari, P.C.McAndrew, P.A.Clarke, S.Linardopoulos, R.J.Griffin, G.W.Aherne, F.I.Raynaud, P.Workman, K.Jones, R.L.van Montfort.

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.