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PDBsum entry 1wbn

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Transferase PDB id
1wbn
Jmol
Contents
Protein chain
352 a.a. *
Ligands
L09
Waters ×552
* Residue conservation analysis
PDB id:
1wbn
Name: Transferase
Title: Fragment based p38 inhibitors
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38alpha, map kinase p38alpha, cytokine suppressive anti-inflammatory drug binding protein, csaid binding protein, csbp, max-interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.4Å     R-factor:   0.180     R-free:   0.243
Authors: A.Cleasby,L.A.Devine,A.L.Gill,H.Jhoti
Key ref: A.L.Gill et al. (2005). Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. J Med Chem, 48, 414-426. PubMed id: 15658855 DOI: 10.1021/jm049575n
Date:
04-Nov-04     Release date:   03-Nov-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
352 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/jm049575n J Med Chem 48:414-426 (2005)
PubMed id: 15658855  
 
 
Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.
A.L.Gill, M.Frederickson, A.Cleasby, S.J.Woodhead, M.G.Carr, A.J.Woodhead, M.T.Walker, M.S.Congreve, L.A.Devine, D.Tisi, M.O'Reilly, L.C.Seavers, D.J.Davis, J.Curry, R.Anthony, A.Padova, C.W.Murray, R.A.Carr, H.Jhoti.
 
  ABSTRACT  
 
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20190518 A.Yamano (2010).
[Fragment-based screening by X-ray structure analysis].
  Yakugaku Zasshi, 130, 335-340.  
20304641 C.S.Leung, J.G.Zeevaart, R.A.Domaoal, M.Bollini, V.V.Thakur, K.A.Spasov, K.S.Anderson, and W.L.Jorgensen (2010).
Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives.
  Bioorg Med Chem Lett, 20, 2485-2488.  
19053779 A.J.Smith, X.Zhang, A.G.Leach, and K.N.Houk (2009).
Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins.
  J Med Chem, 52, 225-233.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19471858 M.H.Seifert (2009).
Robust optimization of scoring functions for a target class.
  J Comput Aided Mol Des, 23, 633-644.  
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.  
18940662 A.C.Dar, M.S.Lopez, and K.M.Shokat (2008).
Small molecule recognition of c-Src via the Imatinib-binding conformation.
  Chem Biol, 15, 1015-1022.
PDB codes: 3el7 3el8
18267130 B.D.Marsden, and S.Knapp (2008).
Doing more than just the structure-structural genomics in kinase drug discovery.
  Curr Opin Chem Biol, 12, 40-45.  
18620864 D.Chen, M.Misra, L.Sower, J.W.Peterson, G.E.Kellogg, and C.H.Schein (2008).
Novel inhibitors of anthrax edema factor.
  Bioorg Med Chem, 16, 7225-7233.  
18342020 J.A.Lewis, E.P.Lebois, and C.W.Lindsley (2008).
Allosteric modulation of kinases and GPCRs: design principles and structural diversity.
  Curr Opin Chem Biol, 12, 269-280.  
18421145 R.E.Hubbard (2008).
Fragment approaches in structure-based drug discovery.
  J Synchrotron Radiat, 15, 227-230.  
17290284 P.J.Hajduk, and J.Greer (2007).
A decade of fragment-based drug design: strategic advances and lessons learned.
  Nat Rev Drug Discov, 6, 211-219.  
17084612 D.A.Erlanson (2006).
Fragment-based lead discovery: a chemical update.
  Curr Opin Biotechnol, 17, 643-652.  
16699182 D.E.Danley (2006).
Crystallization to obtain protein-ligand complexes for structure-aided drug design.
  Acta Crystallogr D Biol Crystallogr, 62, 569-575.  
16317791 D.W.Heinz, M.S.Weiss, and K.U.Wendt (2006).
Biomacromolecular interactions, assemblies and machines: a structural view.
  Chembiochem, 7, 203-208.  
16846802 G.M.Keseru, and G.M.Makara (2006).
Hit discovery and hit-to-lead approaches.
  Drug Discov Today, 11, 741-748.  
16283677 G.Wagner, and S.Laufer (2006).
Small molecular anti-cytokine agents.
  Med Res Rev, 26, 1.  
17108987 I.Collins, and P.Workman (2006).
New approaches to molecular cancer therapeutics.
  Nat Chem Biol, 2, 689-700.  
16492761 J.S.Melnick, J.Janes, S.Kim, J.Y.Chang, D.G.Sipes, D.Gunderson, L.Jarnes, J.T.Matzen, M.E.Garcia, T.L.Hood, R.Beigi, G.Xia, R.A.Harig, H.Asatryan, S.F.Yan, Y.Zhou, X.J.Gu, A.Saadat, V.Zhou, F.J.King, C.M.Shaw, A.I.Su, R.Downs, N.S.Gray, P.G.Schultz, M.Warmuth, and J.S.Caldwell (2006).
An efficient rapid system for profiling the cellular activities of molecular libraries.
  Proc Natl Acad Sci U S A, 103, 3153-3158.  
16374788 M.Vogtherr, K.Saxena, S.Hoelder, S.Grimme, M.Betz, U.Schieborr, B.Pescatore, M.Robin, L.Delarbre, T.Langer, K.U.Wendt, and H.Schwalbe (2006).
NMR characterization of kinase p38 dynamics in free and ligand-bound forms.
  Angew Chem Int Ed Engl, 45, 993-997.
PDB code: 2ewa
16524830 T.L.Blundell, B.L.Sibanda, R.W.Montalvão, S.Brewerton, V.Chelliah, C.L.Worth, N.J.Harmer, O.Davies, and D.Burke (2006).
Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery.
  Philos Trans R Soc Lond B Biol Sci, 361, 413-423.  
16902937 W.T.Mooij, M.J.Hartshorn, I.J.Tickle, A.J.Sharff, M.L.Verdonk, and H.Jhoti (2006).
Automated protein-ligand crystallography for structure-based drug design.
  ChemMedChem, 1, 827-838.  
16783341 Y.Liu, and N.S.Gray (2006).
Rational design of inhibitors that bind to inactive kinase conformations.
  Nat Chem Biol, 2, 358-364.  
15696598 A.Gill, A.Cleasby, and H.Jhoti (2005).
The discovery of novel protein kinase inhibitors by using fragment-based high-throughput x-ray crystallography.
  Chembiochem, 6, 506-512.  
15925537 E.R.Zartler, and M.J.Shapiro (2005).
Fragonomics: fragment-based drug discovery.
  Curr Opin Chem Biol, 9, 366-370.  
15993809 M.Congreve, C.W.Murray, and T.L.Blundell (2005).
Structural biology and drug discovery.
  Drug Discov Today, 10, 895-907.  
16006182 S.P.Williams, L.F.Kuyper, and K.H.Pearce (2005).
Recent applications of protein crystallography and structure-guided drug design.
  Curr Opin Chem Biol, 9, 371-380.  
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.