PDBsum entry 1s3u

Go to PDB code: 
protein ligands links
Oxidoreductase PDB id
Protein chain
186 a.a. *
SO4 ×2
Waters ×52
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Structure determination of tetrahydroquinazoline antifolates in complex with human and pneumocystis carinii dihydrofolate reductase: correlations of enzyme selectivity and stereochemistry
Structure: Dihydrofolate reductase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dhfr. Expressed in: escherichia coli. Expression_system_taxid: 562
2.50Å     R-factor:   0.165     R-free:   0.182
Authors: V.Cody,J.R.Luft,W.Pangborn,A.Gangjee,S.F.Queener
Key ref:
V.Cody et al. (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. PubMed id: 15039552 DOI: 10.1107/S0907444904002094
14-Jan-04     Release date:   30-Mar-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00374  (DYR_HUMAN) -  Dihydrofolate reductase
187 a.a.
186 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Dihydrofolate reductase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Folate Coenzymes
      Reaction: 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH
+ NADP(+)
= 7,8-dihydrofolate
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  


DOI no: 10.1107/S0907444904002094 Acta Crystallogr D Biol Crystallogr 60:646-655 (2004)
PubMed id: 15039552  
Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry.
V.Cody, J.R.Luft, W.Pangborn, A.Gangjee, S.F.Queener.
Structural data are reported for the first examples of the tetrahydroquinazoline antifolate (6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline (1) and its trimethoxy analogue (6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydroquinazoline (2) as inhibitor complexes with dihydrofolate reductase (DHFR) from human (hDHFR) and Pneumocystis carinii (pcDHFR) sources. The indoline analogue (1) was crystallized as ternary complexes with NADPH and hDHFR (1.9 A resolution) and pcDHFR (2.3 A resolution), while the trimethoxy quinazoline analogue (2) was crystallized as a binary complex with hDHFR in two polymorphic rhombohedral R3 lattices: R3(1) to 1.8 A resolution and R3(2) to 2.0 A resolution. Structural analysis of these potent and selective DHFR-inhibitor complexes revealed preferential binding of the 6S-equatorial isomer in each structure. This configuration is similar to that of the natural tetrahydrofolate substrate; that is, 6S. These data also show that in both the hDHFR and pcDHFR ternary complexes with (1) the indoline ring is partially disordered, with two static conformations that differ between structures. These conformers also differ from that observed for the trimethoxybenzyl ring of tetrahydroquinazoline (2). There is also a correlation between the disorder of the flexible loop 23 and the disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1) ternary complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR) sequence with those of other DHFRs provides insight into the role of sequence and conformation in inhibitor-binding preferences which may aid in the design of novel antifolates with specific DHFR selectivity.
  Selected figure(s)  
Figure 2.
Figure 2 Orientation of the pteridine ring for folates (cyan) and antifolates (red). The Connolly surface for hDHFR is shown in green and the contact distances of the nicotinamide ring of NADPH are shown to the folate-reduction site.
Figure 8.
Figure 8 Comparison of the binding of inhibitor (1) to human DHFR (violet) and pcDHFR (yellow). In each structure the indoline ring of (1) is disordered. There are two orientations observed in the human DHFR structure (violet) and two orientations observed in the pcDHFR complex (green and cyan). Diagram 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 (2004, 60, 646-655) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21302360 M.Sáez-Ayala, L.Sánchez-Del-Campo, M.F.Montenegro, S.Chazarra, A.Tárraga, J.Cabezas-Herrera, and J.N.Rodríguez-López (2011).
Comparison of a pair of synthetic tea-catechin-derived epimers: synthesis, antifolate activity, and tyrosinase-mediated activation in melanoma.
  ChemMedChem, 6, 440-449.  
19085027 J.P.Priestle (2009).
3-D clustering: a tool for high throughput docking.
  J Mol Model, 15, 551-560.  
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
20054477 L.Sánchez-Del-Campo, M.Sáez-Ayala, S.Chazarra, J.Cabezas-Herrera, and J.N.Rodríguez-López (2009).
Binding of natural and synthetic polyphenols to human dihydrofolate reductase.
  Int J Mol Sci, 10, 5398-5410.  
18214969 M.Spina, M.Cuccioloni, M.Mozzicafreddo, F.Montecchia, S.Pucciarelli, A.M.Eleuteri, E.Fioretti, and M.Angeletti (2008).
Mechanism of inhibition of wt-dihydrofolate reductase from E. coli by tea epigallocatechin-gallate.
  Proteins, 72, 240-251.  
18536013 N.Schormann, O.Senkovich, K.Walker, D.L.Wright, A.C.Anderson, A.Rosowsky, S.Ananthan, B.Shinkre, S.Velu, and D.Chattopadhyay (2008).
Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function.
  Proteins, 73, 889-901.
PDB codes: 2h2q 3cl9 3clb
17158459 Z.Luka, S.Pakhomova, L.V.Loukachevitch, M.Egli, M.E.Newcomer, and C.Wagner (2007).
5-methyltetrahydrofolate is bound in intersubunit areas of rat liver folate-binding protein glycine N-methyltransferase.
  J Biol Chem, 282, 4069-4075.
PDB codes: 2idj 2idk
17205374 G.A.Landrum, J.E.Penzotti, and S.Putta (2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
  J Comput Aided Mol Des, 20, 751-762.  
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
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.