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PDBsum entry 3cse
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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
3cse

 

 

 

 

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Contents
Protein chains
225 a.a. *
Ligands
NDP ×2
N22 ×2
Waters ×388
* Residue conservation analysis
PDB id:
3cse
Name: Oxidoreductase
Title: Candida glabrata dihydrofolate reductase complexed with NADPH and 2,4- diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (ucp120b)
Structure: Dihydrofolate reductase. Chain: a, b. Engineered: yes
Source: Candida glabrata. Yeast. Organism_taxid: 5478. Gene: dhfr. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.60Å     R-factor:   0.183     R-free:   0.232
Authors: J.Liu,A.C.Anderson
Key ref: J.Liu et al. (2008). Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase. Chem Biol, 15, 990-996. PubMed id: 18804036
Date:
09-Apr-08     Release date:   25-Nov-08    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q6FPH0  (Q6FPH0_CANGA) -  Dihydrofolate reductase from Candida glabrata (strain ATCC 2001 / BCRC 20586 / JCM 3761 / NBRC 0622 / NRRL Y-65 / CBS 138)
Seq:
Struc: 		217 a.a.
225 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.5.1.3  - dihydrofolate reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Folate Coenzymes
      Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
(6S)-5,6,7,8-tetrahydrofolate
 +
NADP(+)
Bound ligand (Het Group name = NDP)
corresponds exactly 		= 7,8-dihydrofolate
 + NADPH
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Chem Biol 15:990-996 (2008)
PubMed id: 18804036  
 
 
Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.
J.Liu, D.B.Bolstad, A.E.Smith, N.D.Priestley, D.L.Wright, A.C.Anderson.
 
  ABSTRACT  
 
Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20026215 K.M.Frey, M.N.Lombardo, D.L.Wright, and A.C.Anderson (2010).
Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase.
  J Struct Biol, 170, 93-97.
PDB code: 3i8a
19950979 J.L.Paulsen, and A.C.Anderson (2009).
Scoring ensembles of docked protein:ligand interactions for virtual lead optimization.
  J Chem Inf Model, 49, 2813-2819.  
19560363 J.L.Paulsen, J.Liu, D.B.Bolstad, A.E.Smith, N.D.Priestley, D.L.Wright, and A.C.Anderson (2009).
In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.
  Bioorg Med Chem, 17, 4866-4872.  
19152636 J.Liu, D.B.Bolstad, A.E.Smith, N.D.Priestley, D.L.Wright, and A.C.Anderson (2009).
Probing the Active Site of Candida glabrata Dihydrofolate Reductase with High Resolution Crystal Structures and the Synthesis of New Inhibitors.
  Chem Biol Drug Des, 73, 62-74.
PDB codes: 3eej 3eek 3eel 3eem
19168759 J.Liu, D.B.Bolstad, E.S.Bolstad, D.L.Wright, and A.C.Anderson (2009).
Towards new antifolates targeting eukaryotic opportunistic infections.
  Eukaryot Cell, 8, 483-486.  
19323450 J.M.Beierlein, L.Deshmukh, K.M.Frey, O.Vinogradova, and A.C.Anderson (2009).
The solution structure of Bacillus anthracis dihydrofolate reductase yields insight into the analysis of structure-activity relationships for novel inhibitors.
  Biochemistry, 48, 4100-4108.
PDB code: 2kgk
19249312 K.M.Frey, J.Liu, M.N.Lombardo, D.B.Bolstad, D.L.Wright, and A.C.Anderson (2009).
Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance.
  J Mol Biol, 387, 1298-1308.
PDB codes: 3f0b 3f0u 3fq0 3fqc 3fqf 3fqo 3fqv 3fqz
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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