PDBsum entry 2zdu

Transferase

PDB id: 2zdu

Contents

Protein chain

330 a.a. *

Ligands

446

Waters ×58

* Residue conservation analysis

PDB id:

2zdu

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:

2.50Å R-factor: 0.241 R-free: 0.319

Authors:

S.Sogabe,T.Ohra,F.Itoh,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 (1). Bioorg Med Chem Lett, 16, 4715-4732. PubMed id: 18313304 DOI: 10.1016/j.bmc.2008.02.027

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: 330 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.2008.02.027

Bioorg Med Chem Lett 16:4715-4732 (2008)

PubMed id: 18313304

Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1).

Y.Asano, S.Kitamura, T.Ohra, K.Aso, H.Igata, T.Tamura, T.Kawamoto, T.Tanaka, S.Sogabe, S.Matsumoto, M.Yamaguchi, H.Kimura, F.Itoh.

ABSTRACT

A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.