PDBsum entry 1wbo

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Transferase PDB id
Protein chain
351 a.a. *
Waters ×331
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Fragment based p38 inhibitors
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: p38 alpha map kinase, mitogen-activated protein kinase p38 alpha, 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.
2.16Å     R-factor:   0.167     R-free:   0.219
Authors: A.Cleasby,L.Devine,A.Gill,H.Jhoti
Key ref: M.J.Hartshorn et al. (2005). Fragment-based lead discovery using X-ray crystallography. J Med Chem, 48, 403-413. PubMed id: 15658854 DOI: 10.1021/jm0495778
04-Nov-04     Release date:   27-Jan-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
360 a.a.
351 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ 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  


DOI no: 10.1021/jm0495778 J Med Chem 48:403-413 (2005)
PubMed id: 15658854  
Fragment-based lead discovery using X-ray crystallography.
M.J.Hartshorn, C.W.Murray, A.Cleasby, M.Frederickson, I.J.Tickle, H.Jhoti.
Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the discovery of novel lead compounds against a range of targets, and the companion paper illustrates how lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.

Literature references that cite this PDB file's key reference

  PubMed id Reference
23060265 G.Bollag, J.Tsai, J.Zhang, C.Zhang, P.Ibrahim, K.Nolop, and P.Hirth (2012).
Vemurafenib: the first drug approved for BRAF-mutant cancer.
  Nat Rev Drug Discov, 11, 873-886.  
21051336 K.Y.Hsin, H.P.Morgan, S.R.Shave, A.C.Hinton, P.Taylor, and M.D.Walkinshaw (2011).
EDULISS: a small-molecule database with data-mining and pharmacophore searching capabilities.
  Nucleic Acids Res, 39, D1042-D1048.  
21536436 P.Vella, W.M.Hussein, E.W.Leung, D.Clayton, D.L.Ollis, N.Mitić, G.Schenk, and R.P.McGeary (2011).
The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening.
  Bioorg Med Chem Lett, 21, 3282-3285.  
20190518 A.Yamano (2010).
[Fragment-based screening by X-ray structure analysis].
  Yakugaku Zasshi, 130, 335-340.  
19960014 J.E.Ladbury, G.Klebe, and E.Freire (2010).
Adding calorimetric data to decision making in lead discovery: a hot tip.
  Nat Rev Drug Discov, 9, 23-27.  
19685275 M.Lisurek, B.Rupp, J.Wichard, M.Neuenschwander, J.P.von Kries, R.Frank, J.Rademann, and R.Kühne (2010).
Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept.
  Mol Divers, 14, 401-408.  
20404926 N.Huang, and M.P.Jacobson (2010).
Binding-site assessment by virtual fragment screening.
  PLoS One, 5, e10109.  
20428531 Y.Lu, Y.Wang, and W.Zhu (2010).
Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design.
  Phys Chem Chem Phys, 12, 4543-4551.  
20686525 Z.Liu, Q.Chai, Y.Y.Li, Q.Shen, L.P.Ma, L.N.Zhang, X.Wang, L.Sheng, J.Y.Li, J.Li, and J.K.Shen (2010).
Discovery of novel PTP1B inhibitors with antihyperglycemic activity.
  Acta Pharmacol Sin, 31, 1005-1012.  
19929835 C.L.Verlinde, E.Fan, S.Shibata, Z.Zhang, Z.Sun, W.Deng, J.Ross, J.Kim, L.Xiao, T.L.Arakaki, J.Bosch, J.M.Caruthers, E.T.Larson, I.Letrong, A.Napuli, A.Kelly, N.Mueller, F.Zucker, W.C.Van Voorhis, E.A.Merritt, and W.G.Hol (2009).
Fragment-based cocktail crystallography by the medical structural genomics of pathogenic protozoa consortium.
  Curr Top Med Chem, 9, 1678-1687.  
18979089 F.Pröll, P.Fechner, and G.Proll (2009).
Direct optical detection in fragment-based screening.
  Anal Bioanal Chem, 393, 1557-1562.  
19427404 G.Chessari, and A.J.Woodhead (2009).
From fragment to clinical candidate--a historical perspective.
  Drug Discov Today, 14, 668-675.  
19443265 Kloe, D.Bailey, R.Leurs, and Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19226504 I.Miyazaki, S.Simizu, K.Ishida, and H.Osada (2009).
On-chip fragment-based approach for discovery of high-affinity bivalent inhibitors.
  Chembiochem, 10, 838-843.  
18613071 Q.S.Du, R.B.Huang, Y.T.Wei, Z.W.Pang, L.Q.Du, and K.C.Chou (2009).
Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.
  J Comput Chem, 30, 295-304.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19305397 Y.Chen, and B.K.Shoichet (2009).
Molecular docking and ligand specificity in fragment-based inhibitor discovery.
  Nat Chem Biol, 5, 358-364.
PDB codes: 3g2y 3g2z 3g30 3g31 3g32 3g34 3g35
18217214 C.Gerlach, H.Broughton, and A.Zaliani (2008).
FTree query construction for virtual screening: a statistical analysis.
  J Comput Aided Mol Des, 22, 111-118.  
18321097 H.Ji, B.Z.Stanton, J.Igarashi, H.Li, P.Martásek, L.J.Roman, T.L.Poulos, and R.B.Silverman (2008).
Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors.
  J Am Chem Soc, 130, 3900-3914.
PDB codes: 3b3m 3b3n
18676450 J.D.Bauman, K.Das, W.C.Ho, M.Baweja, D.M.Himmel, A.D.Clark, D.A.Oren, P.L.Boyer, S.H.Hughes, A.J.Shatkin, and E.Arnold (2008).
Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design.
  Nucleic Acids Res, 36, 5083-5092.
PDB code: 3dlk
19172689 M.Pellecchia, I.Bertini, D.Cowburn, C.Dalvit, E.Giralt, W.Jahnke, T.L.James, S.W.Homans, H.Kessler, C.Luchinat, B.Meyer, H.Oschkinat, J.Peng, H.Schwalbe, and G.Siegal (2008).
Perspectives on NMR in drug discovery: a technique comes of age.
  Nat Rev Drug Discov, 7, 738-745.  
18412174 P.M.Fischer (2008).
Computational chemistry approaches to drug discovery in signal transduction.
  Biotechnol J, 3, 452-470.  
18037921 P.Taylor, E.Blackburn, Y.G.Sheng, S.Harding, K.Y.Hsin, D.Kan, S.Shave, and M.D.Walkinshaw (2008).
Ligand discovery and virtual screening using the program LIDAEUS.
  Br J Pharmacol, 153, S55-S67.  
17637770 A.A.Shelat, and R.K.Guy (2007).
Scaffold composition and biological relevance of screening libraries.
  Nat Chem Biol, 3, 442-446.  
17524728 A.A.Shelat, and R.K.Guy (2007).
The interdependence between screening methods and screening libraries.
  Curr Opin Chem Biol, 11, 244-251.  
17164528 C.W.Chung (2007).
The use of biophysical methods increases success in obtaining liganded crystal structures.
  Acta Crystallogr D Biol Crystallogr, 63, 62-71.  
17657565 E.Evensen, D.Joseph-McCarthy, G.A.Weiss, S.L.Schreiber, and M.Karplus (2007).
Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4.
  J Comput Aided Mol Des, 21, 395-418.  
18061882 G.Siegal, E.Ab, and J.Schultz (2007).
Integration of fragment screening and library design.
  Drug Discov Today, 12, 1032-1039.  
17851109 H.Jhoti, A.Cleasby, M.Verdonk, and G.Williams (2007).
Fragment-based screening using X-ray crystallography and NMR spectroscopy.
  Curr Opin Chem Biol, 11, 485-493.  
17615669 K.Bharatham, N.Bharatham, and K.W.Lee (2007).
Pharmacophore modeling for protein tyrosine phosphatase 1B inhibitors.
  Arch Pharm Res, 30, 533-542.  
18058037 S.C.Almo, J.B.Bonanno, J.M.Sauder, S.Emtage, T.P.Dilorenzo, V.Malashkevich, S.R.Wasserman, S.Swaminathan, S.Eswaramoorthy, R.Agarwal, D.Kumaran, M.Madegowda, S.Ragumani, Y.Patskovsky, J.Alvarado, U.A.Ramagopal, J.Faber-Barata, M.R.Chance, A.Sali, A.Fiser, Z.Y.Zhang, D.S.Lawrence, and S.K.Burley (2007).
Structural genomics of protein phosphatases.
  J Struct Funct Genomics, 8, 121-140.
PDB codes: 1rxd 2fh7 2g59 2hcm 2hhl 2hxp 2hy3 2i0o 2i1y 2i44 2iq1 2irm 2isn 2nv5 2oyc 2p27 2p4u 2p69 2p8e 2pbn 2q5e 2qjc 2r0b
16580603 A.J.Orry, R.A.Abagyan, and C.N.Cavasotto (2006).
Structure-based development of target-specific compound libraries.
  Drug Discov Today, 11, 261-266.  
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.  
16846802 G.M.Keseru, and G.M.Makara (2006).
Hit discovery and hit-to-lead approaches.
  Drug Discov Today, 11, 741-748.  
16249095 I.Collins, J.Caldwell, T.Fonseca, A.Donald, V.Bavetsias, L.J.Hunter, M.D.Garrett, M.G.Rowlands, G.W.Aherne, T.G.Davies, V.Berdini, S.J.Woodhead, D.Davis, L.C.Seavers, P.G.Wyatt, P.Workman, and E.McDonald (2006).
Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
  Bioorg Med Chem, 14, 1255-1273.
PDB codes: 2c1a 2c1b
16902939 J.Degen, and M.Rarey (2006).
FlexNovo: structure-based searching in large fragment spaces.
  ChemMedChem, 1, 854-868.  
16797220 J.J.Irwin (2006).
How good is your screening library?
  Curr Opin Chem Biol, 10, 352-356.  
17072304 K.Babaoglu, and B.K.Shoichet (2006).
Deconstructing fragment-based inhibitor discovery.
  Nat Chem Biol, 2, 720-723.
PDB codes: 2hdq 2hdr 2hds 2hdu
16580974 M.Stahl, W.Guba, and M.Kansy (2006).
Integrating molecular design resources within modern drug discovery research: the Roche experience.
  Drug Discov Today, 11, 326-333.  
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.  
16376818 D.Bousfield (2005).
Microarrays, databases and hard, hard sums.
  Drug Discov Today, 10, 1594-1597.  
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.  
16183020 M.Pellecchia (2005).
Solution nuclear magnetic resonance spectroscopy techniques for probing intermolecular interactions.
  Chem Biol, 12, 961-971.  
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.  
15970264 T.Högberg (2005).
Widening bottlenecks in drug discovery: glimpses from Drug Discovery Technology Europe 2005.
  Drug Discov Today, 10, 820-822.  
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.