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PDBsum entry 2wsa
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Transferase PDB id
2wsa

 

 

 

 

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Contents
Protein chain
411 a.a. *
Ligands
MYA
646
Waters ×556
* Residue conservation analysis
PDB id:
2wsa
Name: Transferase
Title: Crystal structure of leishmania major n-myristoyltransferase (nmt) with bound myristoyl-coa and a pyrazole sulphonamide ligand (ddd85646)
Structure: Glycylpeptide n-tetradecanoyltransferase. Chain: a. Fragment: residues 5-421. Synonym: n-myristoyl transferase. Engineered: yes
Source: Leishmania major. Organism_taxid: 5664. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.60Å     R-factor:   0.177     R-free:   0.213
Authors: D.A.Robinson,S.Brand,A.H.Fairlamb,M.A.J.Ferguson,J.A.Frearson, P.G.Wyatt,Structural Genomics Consortium (Sgc)
Key ref: J.A.Frearson et al. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature, 464, 728-732. PubMed id: 20360736
Date:
04-Sep-09     Release date:   23-Mar-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q4Q5S8  (Q4Q5S8_LEIMA) -  Glycylpeptide N-tetradecanoyltransferase from Leishmania major
Seq:
Struc: 		421 a.a.
411 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.2.3.1.97  - glycylpeptide N-tetradecanoyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N-terminal glycyl-[protein] + tetradecanoyl-CoA = N-tetradecanoylglycyl- [protein] + CoA + H+
N-terminal glycyl-[protein]
 +
tetradecanoyl-CoA
Bound ligand (Het Group name = MYA)
corresponds exactly 		= N-tetradecanoylglycyl- [protein]
 + CoA
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
Nature 464:728-732 (2010)
PubMed id: 20360736  
 
 
N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.
J.A.Frearson, S.Brand, S.P.McElroy, L.A.Cleghorn, O.Smid, L.Stojanovski, H.P.Price, M.L.Guther, L.S.Torrie, D.A.Robinson, I.Hallyburton, C.P.Mpamhanga, J.A.Brannigan, A.J.Wilkinson, M.Hodgkinson, R.Hui, W.Qiu, O.G.Raimi, D.M.van Aalten, R.Brenk, I.H.Gilbert, K.D.Read, A.H.Fairlamb, M.A.Ferguson, D.F.Smith, P.G.Wyatt.
 
  ABSTRACT  
 
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21587297 J.G.Donaldson, and C.L.Jackson (2011).
ARF family G proteins and their regulators: roles in membrane transport, development and disease.
  Nat Rev Mol Cell Biol, 12, 362-375.  
21256128 S.K.Natesan, A.Black, K.R.Matthews, J.C.Mottram, and M.C.Field (2011).
Trypanosoma brucei brucei: endocytic recycling is important for mouse infectivity.
  Exp Parasitol, 127, 777-783.  
  21351219 Y.Jiang, K.L.Morley, J.D.Schrag, and R.J.Kazlauskas (2011).
Different active-site loop orientation in serine hydrolases versus acyltransferases.
  Chembiochem, 12, 768-776.
PDB code: 3ia2
20696141 D.C.Jones, I.Hallyburton, L.Stojanovski, K.D.Read, J.A.Frearson, and A.H.Fairlamb (2010).
Identification of a κ-opioid agonist as a potent and selective lead for drug development against human African trypanosomiasis.
  Biochem Pharmacol, 80, 1478-1486.  
20360728 G.A.Cross (2010).
Drug discovery: Fat-free proteins kill parasites.
  Nature, 464, 689-690.  
20808768 J.D.Durrant, L.Hall, R.V.Swift, M.Landon, A.Schnaufer, and R.E.Amaro (2010).
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.
  PLoS Negl Trop Dis, 4, e803.  
20922062 J.Frearson, and P.Wyatt (2010).
Drug Discovery in Academia- the third way?
  Expert Opin Drug Discov, 5, 909-919.  
20885434 J.Lukeš, and J.Raper (2010).
Prophylactic antiparasitic transgenesis for human parasitic disease?
  Mol Ther, 18, 1745-1747.  
20844428 M.P.Barrett (2010).
Potential new drugs for human African trypanosomiasis: some progress at last.
  Curr Opin Infect Dis, 23, 603-608.  
20669174 R.Metternich, and G.Tarzia (2010).
"Hot spots" in medicinal chemistry.
  ChemMedChem, 5, 1159-1162.  
20559317 R.N.Hannoush, and J.Sun (2010).
The chemical toolbox for monitoring protein fatty acylation and prenylation.
  Nat Chem Biol, 6, 498-506.  
20589793 U.Holzgrabe (2010).
Trypanosomen im Fokus.
  Pharm Unserer Zeit, 39, 261-262.  
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 code is shown on the right.

 

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