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PDBsum entry 1pd8
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Oxidoreductase PDB id
1pd8

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
186 a.a. *
Ligands
NDP
CO4
Waters ×67
* Residue conservation analysis
PDB id:
1pd8
Name: Oxidoreductase
Title: Analysis of three crystal structure determinations of a 5-methyl-6-n- methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase
Structure: Dihydrofolate reductase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dhfr. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.10Å     R-factor:   0.197     R-free:   0.197
Authors: V.Cody,J.R.Luft,W.Pangborn,A.Gangjee
Key ref:
V.Cody et al. (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. PubMed id: 12925791 DOI: 10.1107/S0907444903014963
Date:
19-May-03     Release date:   09-Dec-03    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00374  (DYR_HUMAN) -  Dihydrofolate reductase from Homo sapiens
Seq:
Struc: 		187 a.a.
186 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
Bound ligand (Het Group name = CO4)
matches with 46.34% similarity 		+ NADPH
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1107/S0907444903014963 Acta Crystallogr D Biol Crystallogr 59:1603-1609 (2003)
PubMed id: 12925791  
 
 
Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase.
V.Cody, J.R.Luft, W.Pangborn, A.Gangjee.
 
  ABSTRACT  
 
Structural data are reported for the first example of the potent antifolate inhibitor 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxy-N-methylanilino)methyl]pyrido[2,3-d]pyrimidine (1) in complex with human dihydrofolate reductase (hDHFR) and NADPH. Small differences in crystallization conditions resulted in the growth of two different forms of a binary complex. The structure determination of an additional crystal of a ternary complex of hDHFR with NADPH and (1) grown under similar conditions is also reported. Diffraction data were collected to 2.1 A resolution for an R3 lattice from a hDHFR ternary complex with NADPH and (1) and to 2.2 A resolution from a binary complex. Data were also collected to 2.1 A resolution from a binary complex with hDHFR and (1) in the first example of a tetragonal P4(3)2(1)2 lattice. Comparison of the intermolecular contacts among these structures reveals differences in the backbone conformation (1.9-3.2 A) for flexible loop regions (residues 40-46, 77-83 and 103-107) that reflect differences in the packing environment between the rhombohedral and tetragonal space groups. Analysis of the packing environments shows that the tetragonal lattice is more tightly packed, as reflected in its smaller V(M) value and lower solvent content. The conformation of the inhibitor (1) is similar in all structures and is also similar to that observed for TMQ, the parent quinazoline compound. The activity profile for this series of 5-deaza N-substituted non-classical trimethoxybenzyl antifolates shows that the N10-CH(3) substituted (1) has the greatest potency and selectivity for Toxoplasma gondii DHFR (tgDHFR) compared with its N-H or N-CHO analogs. Models of the tgDHFR active site indicate preferential contacts with (1) that are not present in either the human or Pneumocystis carinii DHFR structures. Differences in the acidic residue (Glu30 versus Asp for tgDHFR) affect the precise positioning of the diaminopyridopyrimidine ring, while changes in other residues, particularly at positions 60 and 64 (Leu versus Met and Asn versus Phe), involve interactions with the trimethoxybenzyl substituents.
 
  Selected figure(s)  
 
Figure 1.
Figure 1 Schematic representation of trimethoprim (TMP), trimetrexate (TMQ) and its pyridopyrimidine N10-substituted analogs. 		Figure 4.
Figure 4 Comparison of active-site binding region of hDHFR with NADPH and antifolate (1) for the R3 lattice (cyan) and for the P4[3]2[1]2 lattice (yellow). Also shown is F31A hDHFR-TMQ (violet). Models were produced with SETOR (Evans, 1993[Evans, S. V. (1993). J. Mol. Graph. 11, 134-138.]).
 
  The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2003, 59, 1603-1609) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
19748785 A.Gangjee, W.Li, L.Lin, Y.Zeng, M.Ihnat, L.A.Warnke, D.W.Green, V.Cody, J.Pace, and S.F.Queener (2009).
Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.
  Bioorg Med Chem, 17, 7324-7336.
PDB codes: 3k45 3k47
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
18473360 E.S.Bolstad, and A.C.Anderson (2008).
In pursuit of virtual lead optimization: the role of the receptor structure and ensembles in accurate docking.
  Proteins, 73, 566-580.  
16039863 A.Gangjee, Y.Zeng, M.Ihnat, L.A.Warnke, D.W.Green, R.L.Kisliuk, and F.T.Lin (2005).
Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity.
  Bioorg Med Chem, 13, 5475-5491.  
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
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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