PDBsum entry 2zdt

Transferase

PDB id: 2zdt

Contents

Protein chain

342 a.a. *

Ligands

46C

GOL

Waters ×162

* Residue conservation analysis

PDB id:

2zdt

Name:

Transferase

Title:

Crystal structure of human jnk3 complexed with an isoquinolone inhibitor

Structure:

Mitogen-activated protein kinase 10. Chain: a. Fragment: residues unp 39-402. Synonym: stress-activated protein kinase jnk3, c-jun n-terminal kinase 3, map kinase p49 3f12. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.00Å R-factor: 0.216 R-free: 0.262

Authors:

S.Sogabe,Y.Asano,S.Fukumoto,N.Habuka,A.Fujishima

Key ref:

Y.Asano et al. (2008). Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2). Bioorg Med Chem Lett, 16, 4699-4714. PubMed id: 18313930 DOI: 10.1016/j.bmc.2008.02.028

Date:

27-Nov-07 Release date: 23-Sep-08

Protein chain

P53779  (MK10_HUMAN) -  Mitogen-activated protein kinase 10 from Homo sapiens

Seq: 464 a.a.

Struc: 342 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated 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

DOI no: 10.1016/j.bmc.2008.02.028

Bioorg Med Chem Lett 16:4699-4714 (2008)

PubMed id: 18313930

Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2).

Y.Asano, S.Kitamura, T.Ohra, F.Itoh, M.Kajino, T.Tamura, M.Kaneko, S.Ikeda, H.Igata, T.Kawamoto, S.Sogabe, S.Matsumoto, T.Tanaka, M.Yamaguchi, H.Kimura, S.Fukumoto.

ABSTRACT

3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model.