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PDBsum entry 1dr1
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Oxidoreductase PDB id
1dr1

 

 

 

 

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Contents
Protein chain
186 a.a. *
Ligands
NAP
HBI
Metals
_CA
Waters ×133
* Residue conservation analysis
PDB id:
1dr1
Name: Oxidoreductase
Title: 2.2 angstroms crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin
Structure: Dihydrofolate reductase. Chain: a. Engineered: yes
Source: Gallus gallus. Chicken. Organism_taxid: 9031. Organ: liver
Resolution:
2.20Å     R-factor:   0.140    
Authors: M.A.Mctigue,J.F.Davies /Ii,B.T.Kaufman,N.-H.Xuong,J.Kraut
Key ref:
M.A.McTigue et al. (1992). Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin. Biochemistry, 31, 7264-7273. PubMed id: 1510919 DOI: 10.1021/bi00147a009
Date:
14-Mar-92     Release date:   31-Oct-93    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P00378  (DYR_CHICK) -  Dihydrofolate reductase from Gallus gallus
Seq:
Struc: 		189 a.a.
186 a.a.
Key:    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 = NAP)
corresponds exactly 		= 7,8-dihydrofolate
 + NADPH
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/bi00147a009 Biochemistry 31:7264-7273 (1992)
PubMed id: 1510919  
 
 
Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin.
M.A.McTigue, J.F.Davies, B.T.Kaufman, J.Kraut.
 
  ABSTRACT  
 
The 2.2-A crystal structure of chicken liver dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a ternary complex with NADP+ and biopterin (a poor substrate). The space group and unit cell are isomorphous with the previously reported structure of chicken liver DHFR complexed with NADPH and phenyltriazine [Volz, K. W., Matthews, D. A., Alden, R. A., Freer, S. T., Hansch, C., Kaufman, B. T., & Kraut, J. (1982) J. Biol. Chem. 257, 2528-2536]. The structure contains an ordered water molecule hydrogen-bonded to both hydroxyls of the biopterin dihydroxypropyl group as well as to O4 and N5 of the biopterin pteridine ring. This water molecule, not observed in previously determined DHFR structures, is positioned to complete a proposed route for proton transfer from the side-chain carboxylate of E30 to N5 of the pteridine ring. Protonation of N5 is believed to occur during the reduction of dihydropteridine substrates. The positions of the NADP+ nicotinamide and biopterin pteridine rings are quite similar to the nicotinamide and pteridine ring positions in the Escherichia coli DHFR.NADP+.folate complex [Bystroff, C., Oatley, S. J., & Kraut, J. (1990) Biochemistry 29, 3263-3277], suggesting that the reduction of biopterin and the reduction of folate occur via similar mechanisms, that the binding geometry of the nicotinamide and pteridine rings is conserved between DHFR species, and that the p-aminobenzoylglutamate moiety of folate is not required for correct positioning of the pteridine ring in ground-state ternary complexes. Instead, binding of the p-aminobenzoylglutamate moiety of folate may induce the side chain of residue 31 (tyrosine or phenylalanine) in vertebrate DHFRs to adopt a conformation in which the opening to the pteridine binding site is too narrow to allow the substrate to diffuse away rapidly. A reverse conformational change of residue 31 is proposed to be required for tetrahydrofolate release.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19478082 J.P.Volpato, B.J.Yachnin, J.Blanchet, V.Guerrero, L.Poulin, E.Fossati, A.M.Berghuis, and J.N.Pelletier (2009).
Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance.
  J Biol Chem, 284, 20079-20089.
PDB code: 3eig
18623072 Z.Gáspári, G.Pál, and A.Perczel (2008).
A redesigned genetic code for selective labeling in protein NMR.
  Bioessays, 30, 772-780.  
17473015 I.V.Khavrutskii, D.J.Price, J.Lee, and C.L.Brooks (2007).
Conformational change of the methionine 20 loop of Escherichia coli dihydrofolate reductase modulates pKa of the bound dihydrofolate.
  Protein Sci, 16, 1087-1100.  
12704428 J.Yuvaniyama, P.Chitnumsub, S.Kamchonwongpaisan, J.Vanichtanankul, W.Sirawaraporn, P.Taylor, M.D.Walkinshaw, and Y.Yuthavong (2003).
Insights into antifolate resistance from malarial DHFR-TS structures.
  Nat Struct Biol, 10, 357-365.
PDB codes: 1j3i 1j3j 1j3k
14622003 M.Garcia-Viloca, D.G.Truhlar, and J.Gao (2003).
Reaction-path energetics and kinetics of the hydride transfer reaction catalyzed by dihydrofolate reductase.
  Biochemistry, 42, 13558-13575.  
12660990 P.Shrimpton, A.Mullaney, and R.K.Allemann (2003).
Functional role for Tyr 31 in the catalytic cycle of chicken dihydrofolate reductase.
  Proteins, 51, 216-223.  
12021443 P.Shrimpton, and R.K.Allemann (2002).
Role of water in the catalytic cycle of E. coli dihydrofolate reductase.
  Protein Sci, 11, 1442-1451.  
11551441 O.A.Santos-Filho, R.B.de Alencastro, and J.D.Figueroa-Villar (2001).
Homology modeling of wild type and pyrimethamine/cycloguanil-cross resistant mutant type Plasmodium falciparum dihydrofolate reductase. A model for antimalarial chemotherapy resistance.
  Biophys Chem, 91, 305-317.  
11076506 B.Almås, K.Toska, K.Teigen, V.Groehn, W.Pfleiderer, A.Martínez, T.Flatmark, and J.Haavik (2000).
A kinetic and conformational study on the interaction of tetrahydropteridines with tyrosine hydroxylase.
  Biochemistry, 39, 13676-13686.  
10882022 G.Rastelli, W.Sirawaraporn, P.Sompornpisut, T.Vilaivan, S.Kamchonwongpaisan, R.Quarrell, G.Lowe, Y.Thebtaranonth, and Y.Yuthavong (2000).
Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with Plasmodium falciparum dihydrofolate reductase: structural basis of antifolate resistance.
  Bioorg Med Chem, 8, 1117-1128.  
10707029 J.D.Szustakowski, and Z.Weng (2000).
Protein structure alignment using a genetic algorithm.
  Proteins, 38, 428-440.  
10997901 T.Doukov, J.Seravalli, J.J.Stezowski, and S.W.Ragsdale (2000).
Crystal structure of a methyltetrahydrofolate- and corrinoid-dependent methyltransferase.
  Structure, 8, 817-830.
PDB code: 1f6y
9753429 K.E.Goodwill, C.Sabatier, and R.C.Stevens (1998).
Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site.
  Biochemistry, 37, 13437-13445.
PDB code: 2toh
9211842 A.D.Mesecar, B.L.Stoddard, and D.E.Koshland (1997).
Orbital steering in the catalytic power of enzymes: small structural changes with large catalytic consequences.
  Science, 277, 202-206.
PDB codes: 1ai2 1ai3
9109647 J.M.Johnson, E.M.Meiering, J.E.Wright, J.Pardo, A.Rosowsky, and G.Wagner (1997).
NMR solution structure of the antitumor compound PT523 and NADPH in the ternary complex with human dihydrofolate reductase.
  Biochemistry, 36, 4399-4411.  
9012674 M.R.Sawaya, and J.Kraut (1997).
Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence.
  Biochemistry, 36, 586-603.
PDB codes: 1dre 1ra1 1ra2 1ra3 1ra8 1ra9 1rb2 1rb3 1rc4 1rd7 1re7 1rf7 1rg7 1rh3 1rx1 1rx2 1rx3 1rx4 1rx5 1rx6 1rx7 1rx8 1rx9
8679526 H.Lee, V.M.Reyes, and J.Kraut (1996).
Crystal structures of Escherichia coli dihydrofolate reductase complexed with 5-formyltetrahydrofolate (folinic acid) in two space groups: evidence for enolization of pteridine O4.
  Biochemistry, 35, 7012-7020.
PDB codes: 1jol 1jom
  8897596 J.D.Cronk, J.A.Endrizzi, and T.Alber (1996).
High-resolution structures of the bifunctional enzyme and transcriptional coactivator DCoH and its complex with a product analogue.
  Protein Sci, 5, 1963-1972.
PDB codes: 1dco 1dcp
7883011 O.Rimet, M.Chauvet, M.Dell'Amico, G.Noat, and M.Bourdeaux (1995).
Variations in fluorescence and enzymic properties of bovine dihydrofolate reductase.NADPH complex during the slow conformational change induced by coenzyme binding.
  Eur J Biochem, 228, 55-59.  
7890613 W.S.Lewis, V.Cody, N.Galitsky, J.R.Luft, W.Pangborn, S.K.Chunduru, H.T.Spencer, J.R.Appleman, and R.L.Blakley (1995).
Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers.
  J Biol Chem, 270, 5057-5064.
PDB codes: 1dlr 1dls
8294945 P.L.Cummins, and J.E.Gready (1993).
Computer-aided drug design: a free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase.
  J Comput Aided Mol Des, 7, 535-555.  
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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