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PDBsum entry 2c7v

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
2c7v
Jmol
Contents
Protein chains
253 a.a. *
Ligands
NAP ×4
MTX ×4
ACT ×2
Metals
_NI ×2
Waters ×799
* Residue conservation analysis
PDB id:
2c7v
Name: Oxidoreductase
Title: Structure of trypanosoma brucei pteridine reductase (ptr1) in ternary complex with cofactor and the antifolate methotrexate
Structure: Pteridine reductase. Chain: a, b, c, d. Engineered: yes
Source: Trypanosoma brucei brucei. Organism_taxid: 5702. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PDB file)
Resolution:
2.2Å     R-factor:   0.157     R-free:   0.223
Authors: A.Dawson,F.Gibellini,N.Sienkiewicz,P.K.Fyfe,K.Mcluskey, A.H.Fairlamb,W.N.Hunter
Key ref: A.Dawson et al. (2006). Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate. Mol Microbiol, 61, 1457-1468. PubMed id: 16968221
Date:
29-Nov-05     Release date:   19-Sep-06    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
O76290  (O76290_TRYBB) -  Pteridine reductase
Seq:
Struc:
268 a.a.
253 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   2 terms 
  Biochemical function     nucleotide binding     2 terms  

 

 
Mol Microbiol 61:1457-1468 (2006)
PubMed id: 16968221  
 
 
Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate.
A.Dawson, F.Gibellini, N.Sienkiewicz, L.B.Tulloch, P.K.Fyfe, K.McLuskey, A.H.Fairlamb, W.N.Hunter.
 
  ABSTRACT  
 
The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP+ and the inhibitor determined at 2.2 A resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the beta6-alpha6 loop and alpha6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21239486 H.B.Ong, N.Sienkiewicz, S.Wyllie, and A.H.Fairlamb (2011).
Dissecting the metabolic roles of pteridine reductase 1 in Trypanosoma brucei and Leishmania major.
  J Biol Chem, 286, 10429-10438.  
19748480 E.J.Shanks, H.B.Ong, D.A.Robinson, S.Thompson, N.Sienkiewicz, A.H.Fairlamb, and J.A.Frearson (2010).
Development and validation of a cytochrome c-coupled assay for pteridine reductase 1 and dihydrofolate reductase.
  Anal Biochem, 396, 194-203.
PDB code: 2vz0
19916554 L.B.Tulloch, V.P.Martini, J.Iulek, J.K.Huggan, J.H.Lee, C.L.Gibson, T.K.Smith, C.J.Suckling, and W.N.Hunter (2010).
Structure-based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases.
  J Med Chem, 53, 221-229.
PDB codes: 3bmc 3bmn 3bmo 3bmq 3jq6 3jq7 3jq8 3jq9 3jqa 3jqb 3jqc 3jqd 3jqe 3jqf 3jqg
20545846 N.Sienkiewicz, H.B.Ong, and A.H.Fairlamb (2010).
Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice.
  Mol Microbiol, 77, 658-671.  
19527033 C.P.Mpamhanga, D.Spinks, L.B.Tulloch, E.J.Shanks, D.A.Robinson, I.T.Collie, A.H.Fairlamb, P.G.Wyatt, J.A.Frearson, W.N.Hunter, I.H.Gilbert, and R.Brenk (2009).
One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening.
  J Med Chem, 52, 4454-4465.
PDB codes: 2wd7 2wd8 3gn1 3gn2
18245389 A.Cavazzuti, G.Paglietti, W.N.Hunter, F.Gamarro, S.Piras, M.Loriga, S.Allecca, P.Corona, K.McLuskey, L.Tulloch, F.Gibellini, S.Ferrari, and M.P.Costi (2008).
Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development.
  Proc Natl Acad Sci U S A, 105, 1448-1453.
PDB codes: 2p8k 2qhx 3h4v
18557814 N.Sienkiewicz, S.Jarosławski, S.Wyllie, and A.H.Fairlamb (2008).
Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes.
  Mol Microbiol, 69, 520-533.  
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.