PDBsum entry 2f7e

Transferase

PDB id: 2f7e

Contents

Protein chains

336 a.a. *

20 a.a. *

Ligands

2EA

Waters ×190

* Residue conservation analysis

PDB id:

2f7e

Name:

Transferase

Title:

Pka complexed with (s)-2-(1h-indol-3-yl)-1-(5-isoquinolin-6-yl- pyridin-3-yloxymethyl-etylamine

Structure:

Camp-dependent protein kinase, alpha-catalytic subunit. Chain: e. Synonym: pka c-alpha. Engineered: yes. Pki inhibitory peptide. Chain: i. Engineered: yes

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Gene: prkaca. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.283 R-free: 0.323

Authors:

V.S.Stoll

Key ref:

Q.Li et al. (2006). Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer. Bioorg Med Chem Lett, 16, 2000-2007. PubMed id: 16413780 DOI: 10.1016/j.bmcl.2005.12.065

Date:

30-Nov-05 Release date: 27-Jun-06

Protein chain

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

Seq: 351 a.a.

Struc: 336 a.a.

Protein chain

P61925  (IPKA_HUMAN) -  cAMP-dependent protein kinase inhibitor alpha from Homo sapiens

Seq: 76 a.a.

Struc: 20 a.a.

Enzyme reactions

• Enzyme class 2: Chain E: 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⁺
• Enzyme class 3: Chain I: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

DOI no: 10.1016/j.bmcl.2005.12.065

Bioorg Med Chem Lett 16:2000-2007 (2006)

PubMed id: 16413780

Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer.

Q.Li, K.W.Woods, S.Thomas, G.D.Zhu, G.Packard, J.Fisher, T.Li, J.Gong, J.Dinges, X.Song, J.Abrams, Y.Luo, E.F.Johnson, Y.Shi, X.Liu, V.Klinghofer, R.Des Jong, T.Oltersdorf, V.S.Stoll, C.G.Jakob, S.H.Rosenberg, V.L.Giranda.

ABSTRACT

Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.