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PDBsum entry 1di9

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protein ligands links
Transferase PDB id
1di9
Jmol
Contents
Protein chain
348 a.a. *
Ligands
MSQ
Waters ×61
* Residue conservation analysis
PDB id:
1di9
Name: Transferase
Title: The structure of p38 mitogen-activated protein kinase in complex with 4-[3-methylsulfanylanilino]-6,7- dimethoxyquinazoline
Structure: P38 kinase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.60Å     R-factor:   0.209     R-free:   0.253
Authors: L.Shewchuk,A.Hassell,L.F.Kuyper
Key ref: L.Shewchuk et al. (2000). Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase. J Med Chem, 43, 133-138. PubMed id: 10633045 DOI: 10.1021/jm990401t
Date:
29-Nov-99     Release date:   29-Nov-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
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: 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: 10.1021/jm990401t J Med Chem 43:133-138 (2000)
PubMed id: 10633045  
 
 
Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase.
L.Shewchuk, A.Hassell, B.Wisely, W.Rocque, W.Holmes, J.Veal, L.F.Kuyper.
 
  ABSTRACT  
 
4-Anilinoquinazolines represent an important class of protein kinase inhibitor. Modes of binding for two members of this inhibitor class were determined by X-ray crystallographic analysis of one inhibitor (4-[3-hydroxyanilino]-6,7-dimethoxyquinazoline) in complex with cyclin-dependent kinase 2 (CDK2) and the other (4-[3-methylsulfanylanilino]-6,7-dimethoxyquinazoline) in complex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoquinazoline was bound in the ATP site with the quinazoline ring system oriented along the peptide strand that links the two domains of the protein and with the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoline accepted a hydrogen bond from a backbone NH (CDK2, Leu-83; p38, Met-109) of the domain connector strand, and aromatic hydrogen atoms at C2 and C8 interacted with backbone carbonyl oxygen atoms of the peptide strand. The anilino group of the CDK2-bound compound was essentially coplanar with the quinazoline ring system and occupied a pocket between Lys-33 and Phe-80. For the p38-bound inhibitor, the anilino group was angled out of plane and was positioned between Lys-53 and Thr-106 in a manner similar to that observed for the aryl substituent of the pyridinylimidazole class of inhibitor.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20735208 C.Theeraladanon, N.Takahashi, M.Shiina, K.Hamada, Y.Takada, H.Endo, U.Tateishi, T.Oka, K.Ogata, and T.Inoue (2010).
Rational approach to the synthesis, evaluation, and (68)ga labeling of a novel 4-anilinoquinoline epidermal growth factor receptor inhibitor as a new imaging agent that selectively targets the epidermal growth factor receptor tyrosine kinase.
  Cancer Biother Radiopharm, 25, 479-485.  
19590909 F.A.Pasha, M.Muddassar, A.K.Srivastava, and S.J.Cho (2010).
In silico QSAR studies of anilinoquinolines as EGFR inhibitors.
  J Mol Model, 16, 263-277.  
20936649 H.Sun, H.Bi, M.Huang, D.Liu, and Z.Qin (2010).
Absorption of CH330331, a novel 4-anilinoquinazoline inhibitor of epidermal growth factor receptor tyrosine kinase: comparative studies using in vitro, in situ and in vivo models.
  Biopharm Drug Dispos, 31, 486-494.  
20042973 S.S.Sridhar, S.J.Hotte, J.L.Chin, G.R.Hudes, R.Gregg, J.Trachtenberg, L.Wang, D.Tran-Thanh, N.A.Pham, M.S.Tsao, D.Hedley, J.E.Dancey, and M.J.Moore (2010).
A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer.
  Am J Clin Oncol, 33, 609-613.  
19778066 J.Michel, J.Tirado-Rives, and W.L.Jorgensen (2009).
Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization.
  J Am Chem Soc, 131, 15403-15411.  
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.  
19737952 T.Bekaii-Saab, J.Markowitz, N.Prescott, W.Sadee, N.Heerema, L.Wei, Z.Dai, A.Papp, A.Campbell, K.Culler, C.Balint, B.O'Neil, R.M.Lee, M.Zalupski, J.Dancey, H.Chen, M.Grever, C.Eng, and M.Villalona-Calero (2009).
A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas.
  Clin Cancer Res, 15, 5895-5901.  
18493974 A.Wissner, and T.S.Mansour (2008).
The development of HKI-272 and related compounds for the treatment of cancer.
  Arch Pharm (Weinheim), 341, 465-477.  
18493651 B.G.Perera, and D.J.Maly (2008).
Design, synthesis and characterization of "clickable" 4-anilinoquinazoline kinase inhibitors.
  Mol Biosyst, 4, 542-550.  
19026174 H.H.Li, H.Huang, X.H.Zhang, X.M.Luo, L.P.Lin, H.L.Jiang, J.Ding, K.X.Chen, and H.Liu (2008).
Discovering novel 3-nitroquinolines as a new class of anticancer agents.
  Acta Pharmacol Sin, 29, 1529-1538.  
18221368 R.D.Mills, C.H.Sim, S.S.Mok, T.D.Mulhern, J.G.Culvenor, and H.C.Cheng (2008).
Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1).
  J Neurochem, 105, 18-33.  
17694525 D.Kuhn, N.Weskamp, E.Hüllermeier, and G.Klebe (2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
  ChemMedChem, 2, 1432-1447.  
17334377 J.A.Blair, D.Rauh, C.Kung, C.H.Yun, Q.W.Fan, H.Rode, C.Zhang, M.J.Eck, W.A.Weiss, and K.M.Shokat (2007).
Structure-guided development of affinity probes for tyrosine kinases using chemical genetics.
  Nat Chem Biol, 3, 229-238.
PDB codes: 2hwo 2hwp 2j5e 2j5f
16374623 A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
  J Mol Model, 12, 422-431.  
16283677 G.Wagner, and S.Laufer (2006).
Small molecular anti-cytokine agents.
  Med Res Rev, 26, 1.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16783341 Y.Liu, and N.S.Gray (2006).
Rational design of inhibitors that bind to inactive kinase conformations.
  Nat Chem Biol, 2, 358-364.  
15742385 O.Prien (2005).
Target-family-oriented focused libraries for kinases--conceptual design aspects and commercial availability.
  Chembiochem, 6, 500-505.  
16245324 S.D.Mooney, M.H.Liang, R.DeConde, and R.B.Altman (2005).
Structural characterization of proteins using residue environments.
  Proteins, 61, 741-747.  
15326593 A.M.Aronov, and G.W.Bemis (2004).
A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.
  Proteins, 57, 36-50.  
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.  
11807175 I.R.Hardcastle, B.T.Golding, and R.J.Griffin (2002).
Designing inhibitors of cyclin-dependent kinases.
  Annu Rev Pharmacol Toxicol, 42, 325-348.  
12196540 J.Stamos, M.X.Sliwkowski, and C.Eigenbrot (2002).
Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.
  J Biol Chem, 277, 46265-46272.
PDB codes: 1m14 1m17
12237154 M.Knockaert, P.Greengard, and L.Meijer (2002).
Pharmacological inhibitors of cyclin-dependent kinases.
  Trends Pharmacol Sci, 23, 417-425.  
12191617 W.A.Denny (2002).
Irreversible inhibitors of the erbB family of protein tyrosine kinases.
  Pharmacol Ther, 93, 253-261.  
11294633 J.F.Goossens, E.Bouey-Bencteux, R.Houssin, J.P.Hénichart, P.Colson, C.Houssier, W.Laine, B.Baldeyrou, and C.Bailly (2001).
DNA interaction of the tyrosine protein kinase inhibitor PD153035 and its N-methyl analogue.
  Biochemistry, 40, 4663-4671.  
11378364 S.Cockerill, C.Stubberfield, J.Stables, M.Carter, S.Guntrip, K.Smith, S.McKeown, R.Shaw, P.Topley, L.Thomsen, K.Affleck, A.Jowett, D.Hayes, M.Willson, P.Woollard, and D.Spalding (2001).
Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2.
  Bioorg Med Chem Lett, 11, 1401-1405.  
11141566 S.T.Davis, B.G.Benson, H.N.Bramson, D.E.Chapman, S.H.Dickerson, K.M.Dold, D.J.Eberwein, M.Edelstein, S.V.Frye, R.T.Gampe Jr, R.J.Griffin, P.A.Harris, A.M.Hassell, W.D.Holmes, R.N.Hunter, V.B.Knick, K.Lackey, B.Lovejoy, M.J.Luzzio, D.Murray, P.Parker, W.J.Rocque, L.Shewchuk, J.M.Veal, D.H.Walker, and L.F.Kuyper (2001).
Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.
  Science, 291, 134-137.
PDB codes: 1fvt 1fvv
11354366 T.M.Sielecki, T.L.Johnson, J.Liu, J.K.Muckelbauer, R.H.Grafstrom, S.Cox, J.Boylan, C.R.Burton, H.Chen, A.Smallwood, C.H.Chang, M.Boisclair, P.A.Benfield, G.L.Trainor, and S.P.Seitz (2001).
Quinazolines as cyclin dependent kinase inhibitors.
  Bioorg Med Chem Lett, 11, 1157-1160.
PDB code: 2b53
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.