PDBsum entry 3hv3

Transferase

PDB id: 3hv3

Contents

Protein chain

335 a.a. *

Ligands

R49

BOG

GOL

Waters ×124

* Residue conservation analysis

PDB id:

3hv3

Name:

Transferase

Title:

Human p38 map kinase in complex with rl49

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. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.00Å R-factor: 0.233 R-free: 0.300

Authors:

C.Gruetter,J.R.Simard,M.Getlik,D.Rauh

Key ref:

S.Klüter et al. (2010). Displacement assay for the detection of stabilizers of inactive kinase conformations. J Med Chem, 53, 357-367. PubMed id: 19928858

Date:

15-Jun-09 Release date: 17-Nov-09

Protein chain

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

Seq: 360 a.a.

Struc: 335 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

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 53:357-367 (2010)

PubMed id: 19928858

Displacement assay for the detection of stabilizers of inactive kinase conformations.

S.Klüter, C.Grütter, T.Naqvi, M.Rabiller, J.R.Simard, V.Pawar, M.Getlik, D.Rauh.

ABSTRACT

Targeting protein kinases with small molecules outside the highly conserved ATP pocket to stabilize inactive kinase conformations is becoming a more desirable approach in kinase inhibitor research, since these molecules have advanced pharmacological properties compared to compounds exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors are often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyrazolourea type III inhibitor and enzyme fragment complementation (EFC) technology that is suitable to screen stabilizers of enzymatically inactive kinases. To validate this assay system, we report the binding characteristics of a series of kinase inhibitors to inactive p38alpha and JNK2. Additionally, we present protein X-ray crystallography studies to examine the binding modes of potent quinoline-based DFG-out binders in p38alpha.