PDBsum entry 3l9n

Transferase/transferase inhibitor

PDB id: 3l9n

Contents

Protein chains

334 a.a. *

19 a.a. *

Ligands

L9N

Waters ×322

* Residue conservation analysis

PDB id:

3l9n

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of pkab3 (pka triple mutant v123a, l173m, q181k) with compound 27

Structure:

Camp-dependent protein kinase catalytic subunit alpha. Chain: a. Synonym: pka c-alpha. Engineered: yes. Mutation: yes. Camp-dependent protein kinase inhibitor alpha. Chain: c. Fragment: sequence database residues 6-25. Synonym: camp-dependent protein kinase inhibitor, muscle/brain

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prkaca, pkaca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: pkia, prkacn1.

Resolution:

2.00Å R-factor: 0.217 R-free: 0.257

Authors:

X.Huang

Key ref:

Q.Zeng et al. (2010). Azole-based inhibitors of AKT/PKB for the treatment of cancer. Bioorg Med Chem Lett, 20, 1559-1564. PubMed id: 20137943

Date:

05-Jan-10 Release date: 19-Jan-11

Protein chain

P17612  (KAPCA_HUMAN) -  cAMP-dependent protein kinase catalytic subunit alpha from Homo sapiens

Seq: 351 a.a.

Struc: 334 a.a.*

Protein chain

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

Seq: 76 a.a.

Struc: 19 a.a.

* PDB and UniProt seqs differ at 4 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⁺

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

reference

Bioorg Med Chem Lett 20:1559-1564 (2010)

PubMed id: 20137943

Azole-based inhibitors of AKT/PKB for the treatment of cancer.

Q.Zeng, J.G.Allen, M.P.Bourbeau, X.Wang, G.Yao, S.Tadesse, J.T.Rider, C.C.Yuan, F.T.Hong, M.R.Lee, S.Zhang, J.A.Lofgren, D.J.Freeman, S.Yang, C.Li, E.Tominey, X.Huang, D.Hoffman, H.K.Yamane, C.Fotsch, C.Dominguez, R.Hungate, X.Zhang.

ABSTRACT

Through a combination of screening and structure-based rational design, we have discovered a series of N(1)-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.