spacer
spacer

PDBsum entry 1ove

Go to PDB code: 
protein ligands links
Transferase PDB id
1ove
Jmol
Contents
Protein chain
349 a.a. *
Ligands
358
GOL
Waters ×288
* Residue conservation analysis
PDB id:
1ove
Name: Transferase
Title: The structure of p38 alpha in complex with a dihydroquinolin
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38, map kinase p cytokine suppressive anti-inflammatory drug binding protein binding protein, csbp, max-interacting protein 2, map kinas engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.10Å     R-factor:   0.192     R-free:   0.233
Authors: C.E.Fitzgerald,S.B.Patel,J.W.Becker,P.M.Cameron,D.Zaller, V.B.Pikounis,S.J.O'Keefe,G.Scapin
Key ref:
C.E.Fitzgerald et al. (2003). Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. Nat Struct Biol, 10, 764-769. PubMed id: 12897767 DOI: 10.1038/nsb949
Date:
26-Mar-03     Release date:   02-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
349 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.24  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cell   8 terms 
  Biological process     intracellular signal transduction   71 terms 
  Biochemical function     nucleotide binding     11 terms  

 

 
    reference    
 
 
DOI no: 10.1038/nsb949 Nat Struct Biol 10:764-769 (2003)
PubMed id: 12897767  
 
 
Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity.
C.E.Fitzgerald, S.B.Patel, J.W.Becker, P.M.Cameron, D.Zaller, V.B.Pikounis, S.J.O'Keefe, G.Scapin.
 
  ABSTRACT  
 
The quinazolinone and pyridol-pyrimidine classes of p38 MAP kinase inhibitors have a previously unseen degree of specificity for p38 over other MAP kinases. Comparison of the crystal structures of p38 bound to four different compounds shows that binding of the more specific molecules is characterized by a peptide flip between Met109 and Gly110. Gly110 is a residue specific to the alpha, beta and gamma isoforms of p38. The delta isoform and the other MAP kinases have bulkier residues in this position. These residues would likely make the peptide flip energetically unfavorable, thus explaining the selectivity of binding. To test this hypothesis, we constructed G110A and G110D mutants of p38 and measured the potency of several compounds against them. The results confirm that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110. This unique mode of binding may be exploited in the design of new p38 inhibitors.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Binding of inhibitors to p38 . Stereo view of the binding sites for the complexes of p38 with (a) compound 1, yellow; (b) compound 2, green24; (c) compound 3, blue; (d) compound 4, magenta. The same coloring scheme is used in all figures. Figures 1b and 2 -4 were prepared with RIBBONS39.
Figure 4.
Figure 4. Binding orientation of 3,4-dihydropyridol[3,2-d]pyrimidine and 2(1H)-quinazolinone to p38 . Surface representation of the inhibitor-binding site: the linker region is red, the glycine-rich loop blue. Compounds 2 (green)24 and 4 (magenta) are shown with their molecular surface outlined.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 764-769) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19942586 D.Huang, T.Zhou, K.Lafleur, C.Nevado, and A.Caflisch (2010).
Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis.
  Bioinformatics, 26, 198-204.  
19846555 M.Renko, J.Sabotic, M.Mihelic, J.Brzin, J.Kos, and D.Turk (2010).
Versatile loops in mycocypins inhibit three protease families.
  J Biol Chem, 285, 308-316.
PDB codes: 3h6q 3h6r 3h6s
19731280 K.Ziegler, D.R.Hauser, A.Unger, W.Albrecht, and S.A.Laufer (2009).
2-Acylaminopyridin-4-ylimidazoles as p38 MAP kinase inhibitors: Design, synthesis, and biological and metabolic evaluations.
  ChemMedChem, 4, 1939-1948.  
19382888 R.M.Eglen, and T.Reisine (2009).
The current status of drug discovery against the human kinome.
  Assay Drug Dev Technol, 7, 22-43.  
20160879 R.S.Armen, J.Chen, and C.L.Brooks (2009).
An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.
  J Chem Theory Comput, 5, 2909-2923.  
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
19514026 S.Kazemi, D.M.Krüger, F.Sirockin, and H.Gohlke (2009).
Elastic potential grids: accurate and efficient representation of intermolecular interactions for fully flexible docking.
  ChemMedChem, 4, 1264-1268.  
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
18074334 A.Wortmann, M.C.Jecklin, D.Touboul, M.Badertscher, and R.Zenobi (2008).
Binding constant determination of high-affinity protein-ligand complexes by electrospray ionization mass spectrometry and ligand competition.
  J Mass Spectrom, 43, 600-608.  
18081134 J.Subramanian, S.Sharma, and C.B-Rao (2008).
Modeling and selection of flexible proteins for structure-based drug design: backbone and side chain movements in p38 MAPK.
  ChemMedChem, 3, 336-344.  
18767165 N.Katayama, M.Orita, T.Yamaguchi, H.Hisamichi, S.Kuromitsu, H.Kurihara, H.Sakashita, Y.Matsumoto, S.Fujita, and T.Niimi (2008).
Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors.
  Proteins, 73, 795-801.
PDB codes: 2z7l 2z8c
17700519 S.Rayter, R.Elliott, J.Travers, M.G.Rowlands, T.B.Richardson, K.Boxall, K.Jones, S.Linardopoulos, P.Workman, W.Aherne, C.J.Lord, and A.Ashworth (2008).
A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D.
  Oncogene, 27, 1036-1044.  
18177852 Y.Liu, L.Martinez, K.Ebine, and M.K.Abe (2008).
Role for mitogen-activated protein kinase p38 alpha in lung epithelial branching morphogenesis.
  Dev Biol, 314, 224-235.  
17074860 C.M.Olson, M.N.Hedrick, H.Izadi, T.C.Bates, E.R.Olivera, and J.Anguita (2007).
p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to Borrelia burgdorferi antigens.
  Infect Immun, 75, 270-277.  
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.  
17541990 S.Margutti, and S.A.Laufer (2007).
Are MAP Kinases Drug Targets? Yes, but Difficult Ones.
  ChemMedChem, 2, 1116-1140.  
16283677 G.Wagner, and S.Laufer (2006).
Small molecular anti-cytokine agents.
  Med Res Rev, 26, 1.  
16892352 S.A.Laufer, S.Margutti, and M.D.Fritz (2006).
Substituted isoxazoles as potent inhibitors of p38 MAP kinase.
  ChemMedChem, 1, 197-207.  
16156785 A.E.Szafranska, and K.N.Dalby (2005).
Kinetic mechanism for p38 MAP kinase alpha. A partial rapid-equilibrium random-order ternary-complex mechanism for the phosphorylation of a protein substrate.
  FEBS J, 272, 4631-4645.  
15748168 C.I.Svensson, B.Fitzsimmons, S.Azizi, H.C.Powell, X.Y.Hua, and T.L.Yaksh (2005).
Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization.
  J Neurochem, 92, 1508-1520.  
15711537 M.A.Fabian, W.H.Biggs, D.K.Treiber, C.E.Atteridge, M.D.Azimioara, M.G.Benedetti, T.A.Carter, P.Ciceri, P.T.Edeen, M.Floyd, J.M.Ford, M.Galvin, J.L.Gerlach, R.M.Grotzfeld, S.Herrgard, D.E.Insko, M.A.Insko, A.G.Lai, J.M.Lélias, S.A.Mehta, Z.V.Milanov, A.M.Velasco, L.M.Wodicka, H.K.Patel, P.P.Zarrinkar, and D.J.Lockhart (2005).
A small molecule-kinase interaction map for clinical kinase inhibitors.
  Nat Biotechnol, 23, 329-336.  
16287858 V.A.Beardmore, H.J.Hinton, C.Eftychi, M.Apostolaki, M.Armaka, J.Darragh, J.McIlrath, J.M.Carr, L.J.Armit, C.Clacher, L.Malone, G.Kollias, and J.S.Arthur (2005).
Generation and characterization of p38beta (MAPK11) gene-targeted mice.
  Mol Cell Biol, 25, 10454-10464.  
15031492 M.E.Noble, J.A.Endicott, and L.N.Johnson (2004).
Protein kinase inhibitors: insights into drug design from structure.
  Science, 303, 1800-1805.  
15056660 S.Parmar, E.Katsoulidis, A.Verma, Y.Li, A.Sassano, L.Lal, B.Majchrzak, F.Ravandi, M.S.Tallman, E.N.Fish, and L.C.Platanias (2004).
Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells.
  J Biol Chem, 279, 25345-25352.  
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.