PDBsum entry 3hrb

Transferase

PDB id: 3hrb

Contents

Protein chain

344 a.a. *

Ligands

I39

Waters ×180

* Residue conservation analysis

PDB id:

3hrb

Name:

Transferase

Title:

P38 kinase crystal structure in complex with small molecule inhibitor

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, cytokine suppressive anti-inflammatory drug-binding protein, csaid-binding protein, csbp, max-interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: the plasmid used is annotated as sareum proprietary

Resolution:

2.20Å R-factor: 0.217 R-free: 0.260

Authors:

V.Segarra,W.Lumeras,B.Vidal,P.Leonard,M.Fisher,M.Lamers

Key ref:

W.Lumeras et al. (2009). Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase. J Med Chem, 52, 5531-5545. PubMed id: 19678708

Date:

09-Jun-09 Release date: 01-Sep-09

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 344 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

J Med Chem 52:5531-5545 (2009)

PubMed id: 19678708

Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase.

W.Lumeras, F.Caturla, L.Vidal, C.Esteve, C.Balagué, A.Orellana, M.Domínguez, R.Roca, J.M.Huerta, N.Godessart, B.Vidal.

ABSTRACT

A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).