PDBsum entry 3uvp

Transferase/transferase inhibitor

PDB id: 3uvp

Contents

Protein chain

334 a.a.

Ligands

048

BOG ×2

Waters ×50

PDB id:

3uvp

Name:

Transferase/transferase inhibitor

Title:

Human p38 map kinase in complex with a benzamide substituted benzosuberone

Structure:

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

Resolution:

2.40Å R-factor: 0.220 R-free: 0.297

Authors:

S.C.Mayer-Wrangowski,A.Richters,C.Gruetter,D.Rauh

Key ref:

K.E.Martz et al. (2012). Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors. J Med Chem, 55, 7862-7874. PubMed id: 22897496

Date:

30-Nov-11 Release date: 07-Nov-12

Protein chain

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

Seq: 360 a.a.

Struc: 334 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 55:7862-7874 (2012)

PubMed id: 22897496

Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors.

K.E.Martz, A.Dorn, B.Baur, V.Schattel, M.I.Goettert, S.C.Mayer-Wrangowski, D.Rauh, S.A.Laufer.

ABSTRACT

The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.