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PDBsum entry 1m7q
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protein ligands links
Transferase PDB id
1m7q

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
348 a.a. *
Ligands
SO4
DQO
Waters ×114
* Residue conservation analysis
PDB id:
1m7q
Name: Transferase
Title: Crystal structure of p38 map kinase in complex with a dihydroquinazolinone inhibitor
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38, map kinase p38, cytokine suppressive anti-inflammatory drug binding protein, csaid binding protein, csbp, max-interacting protein 2, map kinase mxi2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.40Å     R-factor:   0.217     R-free:   0.254
Authors: J.E.Stelmach,L.Liu,S.B.Patel,J.V.Pivnichny,G.Scapin,S.Singh, C.E.C.A.Hop,Z.Wang,P.M.Cameron,E.A.Nichols,S.J.O'Keefe,E.A.O'Neill, D.M.Schmatz,C.D.Schwartz,C.M.Thompson,D.M.Zaller,J.B.Doherty
Key ref: J.E.Stelmach et al. (2003). Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett, 13, 277-280. PubMed id: 12482439 DOI: 10.1016/S0960-894X(02)00752-7
Date:
22-Jul-02     Release date:   11-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens
Seq:
Struc: 		360 a.a.
348 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.24  - mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
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/S0960-894X(02)00752-7 Bioorg Med Chem Lett 13:277-280 (2003)
PubMed id: 12482439  
 
 
Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase.
J.E.Stelmach, L.Liu, S.B.Patel, J.V.Pivnichny, G.Scapin, S.Singh, C.E.Hop, Z.Wang, J.R.Strauss, P.M.Cameron, E.A.Nichols, S.J.O'Keefe, E.A.O'Neill, D.M.Schmatz, C.D.Schwartz, C.M.Thompson, D.M.Zaller, J.B.Doherty.
 
  ABSTRACT  
 
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19590255 B.L.Burnette, S.Selness, R.Devraj, G.Jungbluth, R.Kurumbail, L.Stillwell, G.Anderson, S.Mnich, J.Hirsch, R.Compton, P.De Ciechi, H.Hope, M.Hepperle, R.H.Keith, W.Naing, H.Shieh, J.Portanova, Y.Zhang, J.Zhang, R.M.Leimgruber, and J.Monahan (2009).
SD0006: a potent, selective and orally available inhibitor of p38 kinase.
  Pharmacology, 84, 42-60.  
19622861 S.B.Patel, P.M.Cameron, S.J.O'Keefe, B.Frantz-Wattley, J.Thompson, E.A.O'Neill, T.Tennis, L.Liu, J.W.Becker, and G.Scapin (2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
  Acta Crystallogr D Biol Crystallogr, 65, 777-785.
PDB codes: 3gc7 3gc8 3gc9
19261605 T.Kamenecka, J.Habel, D.Duckett, W.Chen, Y.Y.Ling, B.Frackowiak, R.Jiang, Y.Shin, X.Song, and P.Lograsso (2009).
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
  J Biol Chem, 284, 12853-12861.
PDB codes: 3fi2 3fi3
18566506 J.S.Sack, K.F.Kish, M.Pokross, D.Xie, G.J.Duke, J.A.Tredup, S.E.Kiefer, and J.A.Newitt (2008).
Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase.
  Acta Crystallogr D Biol Crystallogr, 64, 705-710.  
17694525 D.Kuhn, N.Weskamp, E.Hüllermeier, and G.Klebe (2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
  ChemMedChem, 2, 1432-1447.  
17646926 K.H.Kim (2007).
Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?
  J Comput Aided Mol Des, 21, 421-435.  
17203364 R.G.Kulkarni, P.Srivani, G.Achaiah, and G.N.Sastry (2007).
Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study.
  J Comput Aided Mol Des, 21, 155-166.  
16283677 G.Wagner, and S.Laufer (2006).
Small molecular anti-cytokine agents.
  Med Res Rev, 26, 1.  
16984893 Y.Zhao, D.Stoffler, and M.Sanner (2006).
Hierarchical and multi-resolution representation of protein flexibility.
  Bioinformatics, 22, 2768-2774.  
15994249 V.Raia, L.Maiuri, C.Ciacci, I.Ricciardelli, L.Vacca, S.Auricchio, M.Cimmino, M.Cavaliere, M.Nardone, A.Cesaro, J.Malcolm, S.Quaratino, and M.Londei (2005).
Inhibition of p38 mitogen activated protein kinase controls airway inflammation in cystic fibrosis.
  Thorax, 60, 773-780.  
12897767 C.E.Fitzgerald, S.B.Patel, J.W.Becker, P.M.Cameron, D.Zaller, V.B.Pikounis, S.J.O'Keefe, and G.Scapin (2003).
Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity.
  Nat Struct Biol, 10, 764-769.
PDB codes: 1ouk 1ouy 1ove
12848623 G.H.Waetzig, and S.Schreiber (2003).
Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases.
  Aliment Pharmacol Ther, 18, 17-32.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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