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PDBsum entry 3ha8

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Transferase PDB id
3ha8
Jmol
Contents
Protein chain
342 a.a. *
Ligands
5JZ
Waters ×49
* Residue conservation analysis
PDB id:
3ha8
Name: Transferase
Title: The complex structure of the map kinase p38/compound 14b
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha, map ki alpha, cytokine suppressive anti-inflammatory drug-binding csaid-binding protein, csbp, max-interacting protein 2, map mxi2, sapk2a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: csbp, csbp1, csbp2, cspb1, mapk14, mxi2, p38. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.48Å     R-factor:   0.217     R-free:   0.248
Authors: B.Zhao,M.A.Clark
Key ref:
M.A.Clark et al. (2009). Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol, 5, 647-654. PubMed id: 19648931 DOI: 10.1038/nchembio.211
Date:
01-May-09     Release date:   04-Aug-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
342 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: 10.1038/nchembio.211 Nat Chem Biol 5:647-654 (2009)
PubMed id: 19648931  
 
 
Design, synthesis and selection of DNA-encoded small-molecule libraries.
M.A.Clark, R.A.Acharya, C.C.Arico-Muendel, S.L.Belyanskaya, D.R.Benjamin, N.R.Carlson, P.A.Centrella, C.H.Chiu, S.P.Creaser, J.W.Cuozzo, C.P.Davie, Y.Ding, G.J.Franklin, K.D.Franzen, M.L.Gefter, S.P.Hale, N.J.Hansen, D.I.Israel, J.Jiang, M.J.Kavarana, M.S.Kelley, C.S.Kollmann, F.Li, K.Lind, S.Mataruse, P.F.Medeiros, J.A.Messer, P.Myers, H.O'Keefe, M.C.Oliff, C.E.Rise, A.L.Satz, S.R.Skinner, J.L.Svendsen, L.Tang, K.van Vloten, R.W.Wagner, G.Yao, B.Zhao, B.A.Morgan.
 
  ABSTRACT  
 
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
 
  Selected figure(s)  
 
Figure 3.
(a) Selection output from DEL-A selections against Aurora A kinase. Low occurrence molecules (<4 copies) have been removed. Both selections show lines in the cycle 2 plane corresponding to 6-aminoquinoline. In method A, the line comprises 2-methoxyphenethylamine at cycle 3. In method B, there are two lines corresponding to 3,4-dimethoxyaniline and 4-pyrrolidinopiperidine at cycle 3. (b) Histograms showing the total occurrences of cycle 1 synthons after Aurora A selections. Using both methods, 7-AT is the highest occurring cycle 1 synthon. (c) Structures of synthesized compounds and their activity data. The compounds consist of members of both the 7-AT and the 6-aminoquinoline families. (d) Crystal structure of compound 10 bound to Aurora A kinase, showing the 2-fluorophenethylamine moiety exposed to solvent. Image created in Accelrys DS Viewer Pro 5.0.
 
  The above figure is reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2009, 5, 647-654) copyright 2009.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20413343 D.H.Drewry, and R.Macarron (2010).
Enhancements of screening collections to address areas of unmet medical need: an industry perspective.
  Curr Opin Chem Biol, 14, 289-298.  
20851666 G.R.Hicks, and N.V.Raikhel (2010).
Advances in dissecting endomembrane trafficking with small molecules.
  Curr Opin Plant Biol, 13, 706-713.  
20391457 J.Scheuermann, and D.Neri (2010).
DNA-encoded chemical libraries: a tool for drug discovery and for chemical biology.
  Chembiochem, 11, 931-937.  
20949943 L.M.McGregor, D.J.Gorin, C.E.Dumelin, and D.R.Liu (2010).
Interaction-dependent PCR: identification of ligand-target pairs from libraries of ligands and libraries of targets in a single solution-phase experiment.
  J Am Chem Soc, 132, 15522-15524.  
20346729 M.A.Clark (2010).
Selecting chemicals: the emerging utility of DNA-encoded libraries.
  Curr Opin Chem Biol, 14, 396-403.  
21058956 M.N.Gwynn, A.Portnoy, S.F.Rittenhouse, and D.J.Payne (2010).
Challenges of antibacterial discovery revisited.
  Ann N Y Acad Sci, 1213, 5.  
20681606 R.E.Kleiner, C.E.Dumelin, G.C.Tiu, K.Sakurai, and D.R.Liu (2010).
In vitro selection of a DNA-templated small-molecule library reveals a class of macrocyclic kinase inhibitors.
  J Am Chem Soc, 132, 11779-11791.  
20229565 S.Melkko, L.Mannocci, C.E.Dumelin, A.Villa, R.Sommavilla, Y.Zhang, M.G.Grütter, N.Keller, L.Jermutus, R.H.Jackson, J.Scheuermann, and D.Neri (2010).
Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library.
  ChemMedChem, 5, 584-590.  
20154660 T.Kodadek (2010).
Rethinking screening.
  Nat Chem Biol, 6, 162-165.  
19875081 F.Buller, Y.Zhang, J.Scheuermann, J.Schäfer, P.Bühlmann, and D.Neri (2009).
Discovery of TNF inhibitors from a DNA-encoded chemical library based on diels-alder cycloaddition.
  Chem Biol, 16, 1075-1086.  
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.