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PDBsum entry 1cd2
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Oxidoreductase PDB id
1cd2

 

 

 

 

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Contents
Protein chain
206 a.a. *
Ligands
NAP
FOL
Waters ×74
* Residue conservation analysis
PDB id:
1cd2
Name: Oxidoreductase
Title: Ligand induced conformational changes in the crystal structures of pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+
Structure: Dihydrofolate reductase. Chain: a. Synonym: dhfr. Engineered: yes. Other_details: complexed with NADP+ and folate
Source: Pneumocystis carinii. Organism_taxid: 4754. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.20Å     R-factor:   0.198    
Authors: V.Cody,N.Galitsky,J.R.Luft,W.Pangborn,R.L.Blakley,A.Gangjee
Key ref:
V.Cody et al. (1999). Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+. Biochemistry, 38, 4303-4312. PubMed id: 10194348 DOI: 10.1021/bi982728m
Date:
05-Mar-99     Release date:   06-Mar-00    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P16184  (DYR_PNECA) -  Dihydrofolate reductase from Pneumocystis carinii
Seq:
Struc: 		206 a.a.
206 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 = NAP)
corresponds exactly 		=
7,8-dihydrofolate
Bound ligand (Het Group name = FOL)
corresponds exactly 		+ NADPH
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/bi982728m Biochemistry 38:4303-4312 (1999)
PubMed id: 10194348  
 
 
Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.
V.Cody, N.Galitsky, D.Rak, J.R.Luft, W.Pangborn, S.F.Queener.
 
  ABSTRACT  
 
Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of ligand-induced conformational changes in the structure of pcDHFR. These data are also compared with the crystal structure of the ternary complex of methotrexate (MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A resolution. Comparison of the data for the FA binary complex of pcDHFR with those for the ternary structures reveals significant differences, with a >7 A movement of the loop region near residue 23 that results in a new "flap-open" position for the binary complex, and a "closed" position in the ternary complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In the orthorhombic lattice for the binary FA pcDHFR complex, there is also an unwinding of a short helical region near residue 47 that places hydrophobic residues Phe-46 and Phe-49 toward the outer surface, a conformation that is stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+ in the ternary folate pcDHFR complexes shows significant differences in conformation compared with that observed in the MTX-NADPH-pcDHFR ternary complex. Additionally, comparison of the conformations among these four pcDHFR structures reveals evidence for subdomain movement that correlates with cofactor binding states. The larger binding site access in the new "flap-open" loop 23 conformation of the binary FA complex is consistent with the rapid release of cofactor from the product complex during catalysis as well as the more rapid release of substrate product from the binary complex as a result of the weaker contacts of the closed loop 23 conformation, compared to ecDHFR.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
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
18781587 E.S.Bolstad, and A.C.Anderson (2009).
In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking.
  Proteins, 75, 62-74.  
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.  
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.  
18703847 V.Cody, J.Pace, and A.Rosowsky (2008).
Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine.
  Acta Crystallogr D Biol Crystallogr, 64, 977-984.
PDB codes: 3d80 3d84
17019704 V.Cody, J.Pace, K.Chisum, and A.Rosowsky (2006).
New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent 5-(omega-carboxy(alkyloxy) trimethoprim derivatives reveals conformational correlations with activity and novel parallel ring stacking interactions.
  Proteins, 65, 959-969.
PDB codes: 2fzh 2fzi 2fzj
  16511011 A.C.Anderson (2005).
Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 258-262.
PDB code: 1sej
15681865 V.Cody, J.R.Luft, and W.Pangborn (2005).
Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH.
  Acta Crystallogr D Biol Crystallogr, 61, 147-155.
PDB codes: 1u70 1u71 1u72
15504856 A.Nahimana, M.Rabodonirina, J.Bille, P.Francioli, and P.M.Hauser (2004).
Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis.
  Antimicrob Agents Chemother, 48, 4301-4305.  
15039552 V.Cody, J.R.Luft, W.Pangborn, A.Gangjee, and S.F.Queener (2004).
Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry.
  Acta Crystallogr D Biol Crystallogr, 60, 646-655.
PDB codes: 1s3u 1s3v 1s3w 1s3y
14736206 A.Nahimana, M.Rabodonirina, P.Francioli, J.Bille, and P.M.Hauser (2003).
Pneumocystis jirovecii dihydrofolate reductase polymorphisms associated with failure of prophylaxis.
  J Eukaryot Microbiol, 50, 656-657.  
12925782 H.Zhao, T.Bray, M.Ouellette, M.Zhao, R.A.Ferre, D.Matthews, J.M.Whiteley, and K.I.Varughese (2003).
Structure of pteridine reductase (PTR1) from Leishmania tarentolae.
  Acta Crystallogr D Biol Crystallogr, 59, 1539-1544.
PDB code: 1p33
14555647 R.H.O'Neil, R.H.Lilien, B.R.Donald, R.M.Stroud, and A.C.Anderson (2003).
Phylogenetic classification of protozoa based on the structure of the linker domain in the bifunctional enzyme, dihydrofolate reductase-thymidylate synthase.
  J Biol Chem, 278, 52980-52987.
PDB code: 1qzf
14736160 R.H.O'Neil, R.H.Lilien, B.R.Donald, R.M.Stroud, and A.C.Anderson (2003).
The crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveals a novel architecture for the bifunctional enzyme.
  J Eukaryot Microbiol, 50, 555-556.  
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
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.  
12146958 L.Y.Lin, T.Sulea, R.Szittner, C.Kor, E.O.Purisima, and E.A.Meighen (2002).
Implications of the reactive thiol and the proximal non-proline cis-peptide bond in the Structure and function of Vibrio harveyi luciferase.
  Biochemistry, 41, 9938-9945.  
12037296 V.Cody, N.Galitsky, J.R.Luft, W.Pangborn, A.Rosowsky, and S.F.Queener (2002).
Structure-based enzyme inhibitor design: modeling studies and crystal structure analysis of Pneumocystis carinii dihydrofolate reductase ternary complex with PT653 and NADPH.
  Acta Crystallogr D Biol Crystallogr, 58, 946-954.
PDB code: 1klk
12198294 V.Cody, N.Galitsky, J.R.Luft, W.Pangborn, S.F.Queener, and A.Gangjee (2002).
Analysis of quinazoline and pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase.
  Acta Crystallogr D Biol Crystallogr, 58, 1393-1399.
PDB codes: 1ly3 1ly4
11502523 Y.Wang, J.A.Bruenn, S.F.Queener, and V.Cody (2001).
Isolation of rat dihydrofolate reductase gene and characterization of recombinant enzyme.
  Antimicrob Agents Chemother, 45, 2517-2523.  
10736154 V.Cody, D.Chan, N.Galitsky, D.Rak, J.R.Luft, W.Pangborn, S.F.Queener, C.A.Laughton, and M.F.Stevens (2000).
Structural studies on bioactive compounds. 30. Crystal structure and molecular modeling studies on the Pneumocystis carinii dihydrofolate reductase cofactor complex with TAB, a highly selective antifolate.
  Biochemistry, 39, 3556-3564.
PDB codes: 1d8r 1vj3
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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