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PDBsum entry 1ia4
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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1ia4

 

 

 

 

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Contents
Protein chains
192 a.a. *
Ligands
NDP ×2
TQ6 ×2
MES ×2
Waters ×331
* Residue conservation analysis
PDB id:
1ia4
Name: Oxidoreductase
Title: Candida albicans dihydrofolate reductase complex in which the dihydronicotinamide moiety of dihydro-nicotinamide-adenine- dinucleotide phosphate (NADPH) is displaced by 5-{[4-(4-morpholinyl) phenyl]sulfanyl}-2,4-quinazolinediamin (gw2021)
Structure: Dihydrofolate reductase. Chain: a, b. Engineered: yes
Source: Candida albicans. Organism_taxid: 5476. Gene: dfr1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.85Å     R-factor:   0.159    
Authors: M.Whitlow,A.J.Howard,L.F.Kuyper
Key ref: M.Whitlow et al. (2001). X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor. J Med Chem, 44, 2928-2932. PubMed id: 11520201 DOI: 10.1021/jm0101444
Date:
22-Mar-01     Release date:   11-Apr-01    
PROCHECK
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 Headers
 References

Protein chains
P22906  (DYR_CANAX) -  Dihydrofolate reductase from Candida albicans
Seq:
Struc: 		192 a.a.
192 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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)
matches with 72.92% similarity 		= 7,8-dihydrofolate
 + NADPH
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm0101444 J Med Chem 44:2928-2932 (2001)
PubMed id: 11520201  
 
 
X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor.
M.Whitlow, A.J.Howard, D.Stewart, K.D.Hardman, J.H.Chan, D.P.Baccanari, R.L.Tansik, J.S.Hong, L.F.Kuyper.
 
  ABSTRACT  
 
X-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19364848 C.R.Bourne, R.A.Bunce, P.C.Bourne, K.D.Berlin, E.W.Barrow, and W.W.Barrow (2009).
Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.
  Antimicrob Agents Chemother, 53, 3065-3073.
PDB codes: 3fl8 3fl9
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.  
18804036 J.Liu, D.B.Bolstad, A.E.Smith, N.D.Priestley, D.L.Wright, and A.C.Anderson (2008).
Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.
  Chem Biol, 15, 990-996.
PDB code: 3cse
18061917 S.Henrich, S.Richter, and R.C.Wade (2008).
On the use of PIPSA to guide target-selective drug design.
  ChemMedChem, 3, 413-417.  
17334823 K.H.Kim (2007).
Outliers in SAR and QSAR: is unusual binding mode a possible source of outliers?
  J Comput Aided Mol Des, 21, 63-86.  
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
Evaluation of library ranking efficacy in virtual screening.
  J Comput Chem, 26, 11-22.  
16048931 O.Senkovich, V.Bhatia, N.Garg, and D.Chattopadhyay (2005).
Lipophilic antifolate trimetrexate is a potent inhibitor of Trypanosoma cruzi: prospect for chemotherapy of Chagas' disease.
  Antimicrob Agents Chemother, 49, 3234-3238.  
16170052 R.Brenk, J.J.Irwin, and B.K.Shoichet (2005).
Here be dragons: docking and screening in an uncharted region of chemical space.
  J Biomol Screen, 10, 667-674.  
14966133 R.Shi, and S.X.Lin (2004).
Cofactor hydrogen bonding onto the protein main chain is conserved in the short chain dehydrogenase/reductase family and contributes to nicotinamide orientation.
  J Biol Chem, 279, 16778-16785.
PDB codes: 1qyv 1qyw 1qyx
12192068 C.A.Bottoms, P.E.Smith, and J.J.Tanner (2002).
A structurally conserved water molecule in Rossmann dinucleotide-binding domains.
  Protein Sci, 11, 2125-2137.  
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.

 

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