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PDBsum entry 1dhf

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protein ligands Protein-protein interface(s) links
Oxido-reductase PDB id
1dhf
Jmol
Contents
Protein chain
182 a.a. *
Ligands
FOL ×2
Waters ×116
* Residue conservation analysis
PDB id:
1dhf
Name: Oxido-reductase
Title: Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazofolate
Structure: Dihydrofolate reductase. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
2.30Å     R-factor:   0.176    
Authors: J.F.Davies /Ii,J.Kraut
Key ref:
J.F.Davies et al. (1990). Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. Biochemistry, 29, 9467-9479. PubMed id: 2248959 DOI: 10.1021/bi00492a021
Date:
25-Oct-89     Release date:   15-Jul-90    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00374  (DYR_HUMAN) -  Dihydrofolate reductase
Seq:
Struc:
187 a.a.
182 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: 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate
Bound ligand (Het Group name = FOL)
corresponds exactly
+ NADP(+)
= 7,8-dihydrofolate
+ NADPH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cellular_component   3 terms 
  Biological process     small molecule metabolic process   16 terms 
  Biochemical function     drug binding     6 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi00492a021 Biochemistry 29:9467-9479 (1990)
PubMed id: 2248959  
 
 
Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate.
J.F.Davies, T.J.Delcamp, N.J.Prendergast, V.A.Ashford, J.H.Freisheim, J.Kraut.
 
  ABSTRACT  
 
The 2.3-A crystal structure of recombinant human dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a binary complex with folate (a poor substrate at neutral pH) and also as a binary complex with an inhibitor, 5-deazafolate. The inhibitor appears to be protonated at N8 on binding, whereas folate is not. Rotation of the peptide plane joining I7 and V8 from its position in the folate complex permits hydrogen bonding of 5-deazafolate's protonated N8 to the backbone carbonyl of I7, thus contributing to the enzyme's greater affinity for 5-deazafolate than for folate. In this respect it is likely that bound 5-deazafolate furnishes a model for 7,8-dihydrofolate binding and, in addition, resembles the transition state for folate reduction. A hypothetical transition-state model for folate reduction, generated by superposition of the DHFR binary complexes human.5-deazafolate and chicken liver.NADPH, reveals a 1-A overlap of the binding sites for folate's pteridine ring and the dihydronicotinamide ring of NADPH. It is proposed that this binding-site overlap accelerates the reduction of both folate and 7,8-dihydrofolate by simultaneously binding substrate and cofactor with a sub van der Waals separation that is optimal for hydride transfer.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21474759 G.Bhabha, J.Lee, D.C.Ekiert, J.Gam, I.A.Wilson, H.J.Dyson, S.J.Benkovic, and P.E.Wright (2011).
A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis.
  Science, 332, 234-238.
PDB codes: 3ql0 3ql3
20092323 A.Gangjee, N.Zaware, S.Raghavan, M.Ihnat, S.Shenoy, and R.L.Kisliuk (2010).
Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
  J Med Chem, 53, 1563-1578.  
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
19343764 Y.Tanrikulu, E.Proschak, T.Werner, T.Geppert, N.Todoroff, A.Klenner, T.Kottke, K.Sander, E.Schneider, R.Seifert, H.Stark, T.Clark, and G.Schneider (2009).
Homology model adjustment and ligand screening with a pseudoreceptor of the human histamine H4 receptor.
  ChemMedChem, 4, 820-827.  
17516427 E.Proschak, M.Rupp, S.Derksen, and G.Schneider (2008).
Shapelets: possibilities and limitations of shape-based virtual screening.
  J Comput Chem, 29, 108-114.  
  19238244 V.Srivastava, A.Kumar, B.N.Mishra, and M.I.Siddiqi (2008).
Molecular docking studies on DMDP derivatives as human DHFR inhibitors.
  Bioinformation, 3, 180-188.  
16708362 N.Hirano, T.Sawasaki, Y.Tozawa, Y.Endo, and K.Takai (2006).
Tolerance for random recombination of domains in prokaryotic and eukaryotic translation systems: Limited interdomain misfolding in a eukaryotic translation system.
  Proteins, 64, 343-354.  
16640331 S.Zhang, A.Golbraikh, and A.Tropsha (2006).
Development of quantitative structure-binding affinity relationship models based on novel geometrical chemical descriptors of the protein-ligand interfaces.
  J Med Chem, 49, 2713-2724.  
16156893 E.García-Fruitós, N.González-Montalbán, M.Morell, A.Vera, R.M.Ferraz, A.Arís, S.Ventura, and A.Villaverde (2005).
Aggregation as bacterial inclusion bodies does not imply inactivation of enzymes and fluorescent proteins.
  Microb Cell Fact, 4, 27.  
16222560 N.V.Kovalevskaya, Y.D.Smurnyy, V.I.Polshakov, B.Birdsall, A.F.Bradbury, T.Frenkiel, and J.Feeney (2005).
Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH.
  J Biomol NMR, 33, 69-72.
PDB code: 1yho
16100277 S.R.Ainavarapu, L.Li, C.L.Badilla, and J.M.Fernandez (2005).
Ligand binding modulates the mechanical stability of dihydrofolate reductase.
  Biophys J, 89, 3337-3344.  
15229890 M.Barbany, H.Gutiérrez-de-Terán, F.Sanz, and J.Villà-Freixa (2004).
Towards a MIP-based alignment and docking in computer-aided drug design.
  Proteins, 56, 585-594.  
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.  
12925791 V.Cody, J.R.Luft, W.Pangborn, and A.Gangjee (2003).
Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase.
  Acta Crystallogr D Biol Crystallogr, 59, 1603-1609.
PDB codes: 1pd8 1pd9 1pdb
12657784 V.Cody, N.Galitsky, J.R.Luft, W.Pangborn, and A.Gangjee (2003).
Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase.
  Acta Crystallogr D Biol Crystallogr, 59, 654-661.
PDB codes: 1mvs 1mvt
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.  
11266600 V.F.Smith, and C.R.Matthews (2001).
Testing the role of chain connectivity on the stability and structure of dihydrofolate reductase from E. coli: fragment complementation and circular permutation reveal stable, alternatively folded forms.
  Protein Sci, 10, 116-128.  
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
10632709 V.K.Walker, M.G.Tyshenko, M.J.Kuiper, R.V.Dargar, D.A.Yuhas, P.A.Cruickshank, and R.Chaguturu (2000).
Tobacco budworm dihydrofolate reductase is a promising target for insecticide discovery.
  Eur J Biochem, 267, 394-403.  
  10527466 D.S.Goodsell (1999).
The molecular perspective: methotrexate.
  Stem Cells, 17, 314-315.  
10606510 S.E.Greasley, M.M.Yamashita, H.Cai, S.J.Benkovic, D.L.Boger, and I.A.Wilson (1999).
New insights into inhibitor design from the crystal structure and NMR studies of Escherichia coli GAR transformylase in complex with beta-GAR and 10-formyl-5,8,10-trideazafolic acid.
  Biochemistry, 38, 16783-16793.
PDB codes: 1c2t 1c3e
10194348 V.Cody, N.Galitsky, D.Rak, J.R.Luft, W.Pangborn, and S.F.Queener (1999).
Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.
  Biochemistry, 38, 4303-4312.
PDB codes: 1cd2 1e26 2cd2 3cd2 4cd2
10625463 V.I.Polshakov, B.Birdsall, and J.Feeney (1999).
Characterization of rates of ring-flipping in trimethoprim in its ternary complexes with Lactobacillus casei dihydrofolate reductase and coenzyme analogues.
  Biochemistry, 38, 15962-15969.  
9618466 X.Sun, A.L.Bognar, E.N.Baker, and C.A.Smith (1998).
Structural homologies with ATP- and folate-binding enzymes in the crystal structure of folylpolyglutamate synthetase.
  Proc Natl Acad Sci U S A, 95, 6647-6652.
PDB code: 1fgs
9159107 C.Frieden, and A.C.Clark (1997).
Protein folding: how the mechanism of GroEL action is defined by kinetics.
  Proc Natl Acad Sci U S A, 94, 5535-5538.  
8999931 H.Park, P.Zhuang, R.Nichols, and E.E.Howell (1997).
Mechanistic studies of R67 dihydrofolate reductase. Effects of pH and an H62C mutation.
  J Biol Chem, 272, 2252-2258.  
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
9037009 M.S.Goldberg, J.Zhang, S.Sondek, C.R.Matthews, R.O.Fox, and A.L.Horwich (1997).
Native-like structure of a protein-folding intermediate bound to the chaperonin GroEL.
  Proc Natl Acad Sci U S A, 94, 1080-1085.  
9136868 R.Gachhui, D.K.Ghosh, C.Wu, J.Parkinson, B.R.Crane, and D.J.Stuehr (1997).
Mutagenesis of acidic residues in the oxygenase domain of inducible nitric-oxide synthase identifies a glutamate involved in arginine binding.
  Biochemistry, 36, 5097-5103.  
8639551 A.C.Clark, E.Hugo, and C.Frieden (1996).
Determination of regions in the dihydrofolate reductase structure that interact with the molecular chaperonin GroEL.
  Biochemistry, 35, 5893-5901.  
8634297 B.A.Posner, L.Li, R.Bethell, T.Tsuji, and S.J.Benkovic (1996).
Engineering specificity for folate into dihydrofolate reductase from Escherichia coli.
  Biochemistry, 35, 1653-1663.  
8877811 D.A.Gschwend, A.C.Good, and I.D.Kuntz (1996).
Molecular docking towards drug discovery.
  J Mol Recognit, 9, 175-186.  
8885833 G.Scapin, S.G.Reddy, and J.S.Blanchard (1996).
Three-dimensional structure of meso-diaminopimelic acid dehydrogenase from Corynebacterium glutamicum.
  Biochemistry, 35, 13540-13551.
PDB code: 1dap
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
8628226 I.M.Schlichtherle, D.S.Roos, and J.L.Van Houten (1996).
Cloning and molecular analysis of the bifunctional dihydrofolate reductase-thymidylate synthase gene in the ciliated protozoan Paramecium tetraurelia.
  Mol Gen Genet, 250, 665-673.  
  8976559 M.Gross, C.V.Robinson, M.Mayhew, F.U.Hartl, and S.E.Radford (1996).
Significant hydrogen exchange protection in GroEL-bound DHFR is maintained during iterative rounds of substrate cycling.
  Protein Sci, 5, 2506-2513.  
8639582 M.Trujillo, R.G.Donald, D.S.Roos, P.J.Greene, and D.V.Santi (1996).
Heterologous expression and characterization of the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of Toxoplasma gondii.
  Biochemistry, 35, 6366-6374.  
8841139 R.B.Rose, C.S.Craik, N.L.Douglas, and R.M.Stroud (1996).
Three-dimensional structures of HIV-1 and SIV protease product complexes.
  Biochemistry, 35, 12933-12944.
PDB codes: 1ytg 1yth 1yti 1ytj
8784197 T.D.Bradrick, J.M.Beechem, and E.E.Howell (1996).
Unusual binding stoichiometries and cooperativity are observed during binary and ternary complex formation in the single active pore of R67 dihydrofolate reductase, a D2 symmetric protein.
  Biochemistry, 35, 11414-11424.  
8523045 M.T.Barakat, and P.M.Dean (1995).
The atom assignment problem in automated de novo drug design. 3. Algorithms for optimization of fragment placement onto 3D molecular graphs.
  J Comput Aided Mol Des, 9, 359-372.  
8594162 M.T.Barakat, and P.M.Dean (1995).
The atom assignment problem in automated de novo drug design. 4. Tests for site-directed fragment placement based on molecular complementarity.
  J Comput Aided Mol Des, 9, 448-456.  
  7726158 P.Goyette, P.Frosst, D.S.Rosenblatt, and R.Rozen (1995).
Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.
  Am J Hum Genet, 56, 1052-1059.  
8595137 P.Willett (1995).
Genetic algorithms in molecular recognition and design.
  Trends Biotechnol, 13, 516-521.  
7656037 D.R.Knighton, C.C.Kan, E.Howland, C.A.Janson, Z.Hostomska, K.M.Welsh, and D.A.Matthews (1994).
Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase.
  Nat Struct Biol, 1, 186-194.  
7866743 J.N.Champness, A.Achari, S.P.Ballantine, P.K.Bryant, C.J.Delves, and D.K.Stammers (1994).
The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution.
  Structure, 2, 915-924.
PDB code: 1dyr
7876898 P.L.Chau, and P.M.Dean (1994).
Electrostatic complementarity between proteins and ligands. 1. Charge disposition, dielectric and interface effects.
  J Comput Aided Mol Des, 8, 513-525.  
7876899 P.L.Chau, and P.M.Dean (1994).
Electrostatic complementarity between proteins and ligands. 2. Ligand moieties.
  J Comput Aided Mol Des, 8, 527-544.  
7876900 P.L.Chau, and P.M.Dean (1994).
Electrostatic complementarity between proteins and ligands. 3. Structural basis.
  J Comput Aided Mol Des, 8, 545-564.  
8265628 A.P.Dicker, M.C.Waltham, M.Volkenandt, B.I.Schweitzer, G.M.Otter, F.A.Schmid, F.M.Sirotnak, and J.R.Bertino (1993).
Methotrexate resistance in an in vivo mouse tumor due to a non-active-site dihydrofolate reductase mutation.
  Proc Natl Acad Sci U S A, 90, 11797-11801.  
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.  
8460112 P.L.Cummins, and J.E.Gready (1993).
Novel mechanism-based substrates of dihydrofolate reductase and the thermodynamics of ligand binding: a comparison of theory and experiment for 8-methylpterin and 6,8-dimethylpterin.
  Proteins, 15, 426-435.  
1528078 M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.
  Med Res Rev, 12, 317-372.  
1474395 Y.Kato, A.Inoue, M.Yamada, N.Tomioka, and A.Itai (1992).
Automatic superposition of drug molecules based on their common receptor site.
  J Comput Aided Mol Des, 6, 475-486.  
1862073 J.Bajorath, J.Kraut, Z.Q.Li, D.H.Kitson, and A.T.Hagler (1991).
Theoretical studies on the dihydrofolate reductase mechanism: electronic polarization of bound substrates.
  Proc Natl Acad Sci U S A, 88, 6423-6426.  
1765127 R.J.Breckenridge (1991).
Molecular recognition: models for drug design.
  Experientia, 47, 1148-1161.  
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.