PDBsum entry 3p78

Transferase/transferase inhibitor

PDB id: 3p78

Contents

Protein chain

332 a.a.

Ligands

BOG

P78

PDB id:

3p78

Name:

Transferase/transferase inhibitor

Title:

P38 inhibitor-bound

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: map kinase 14, mapk 14, crk1, mitogen-activated protein kinase p38 alpha, map kinase p38 alpha. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: mapk14, crk1, csbp1, csbp2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.247 R-free: 0.313

Authors:

K.K.Moffett,H.Namboodiri

Key ref:

K.Moffett et al. (2011). Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD). Bioorg Med Chem Lett, 21, 7155-7165. PubMed id: 22014550

Date:

12-Oct-10 Release date: 12-Oct-11

Protein chain

P47811  (MK14_MOUSE) -  Mitogen-activated protein kinase 14 from Mus musculus

Seq: 360 a.a.

Struc: 332 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

Bioorg Med Chem Lett 21:7155-7165 (2011)

PubMed id: 22014550

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

K.Moffett, Z.Konteatis, D.Nguyen, R.Shetty, J.Ludington, T.Fujimoto, K.J.Lee, X.Chai, H.Namboodiri, M.Karpusas, B.Dorsey, F.Guarnieri, M.Bukhtiyarova, E.Springman, E.Michelotti.

ABSTRACT

Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.