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Oxidoreductase PDB id
1gyq
Jmol
Contents
Protein chains
358 a.a. *
Ligands
NBD ×4
* Residue conservation analysis
PDB id:
1gyq
Name: Oxidoreductase
Title: Crystal structure of glycosomal glyceraldehyde from leishmania mexicana in complex with n6-benzyl-NAD
Structure: Protein (glyceraldehyde-3-phosphate dehydrogenase). Chain: a, b, c, d. Synonym: gapdh. Engineered: yes
Source: Leishmania mexicana. Organism_taxid: 5665. Gene: glyceraldehyde-3-phosphateurce 6 dehydrogenase. Expressed in: escherichia coli. Expression_system_taxid: 562. Dehydrogenase
Biol. unit: Tetramer (from PDB file)
Resolution:
3.40Å     R-factor:   not given    
Authors: S.Suresh,W.Hol
Key ref:
A.M.Aronov et al. (1999). Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci U S A, 96, 4273-4278. PubMed id: 10200252 DOI: 10.1073/pnas.96.8.4273
Date:
05-Mar-99     Release date:   16-Mar-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q27890  (G3PG_LEIME) -  Glyceraldehyde-3-phosphate dehydrogenase, glycosomal
Seq:
Struc: 		361 a.a.
358 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.2.1.12  - Glyceraldehyde-3-phosphate dehydrogenase (phosphorylating).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Glyceraldehyde-3-phosphate Dehydrogenase (phosphorylating)
      Reaction: D-glyceraldehyde 3-phosphate + phosphate + NAD+ = 3-phospho-D-glyceroyl phosphate + NADH
D-glyceraldehyde 3-phosphate
 + phosphate
 +
NAD(+)
Bound ligand (Het Group name = NBD)
matches with 86.00% similarity 		= 3-phospho-D-glyceroyl phosphate
 + NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     glycosome   2 terms 
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     nucleotide binding     6 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.96.8.4273 Proc Natl Acad Sci U S A 96:4273-4278 (1999)
PubMed id: 10200252  
 
 
Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase.
A.M.Aronov, S.Suresh, F.S.Buckner, W.C.Van Voorhis, C.L.Verlinde, F.R.Opperdoes, W.G.Hol, M.H.Gelb.
 
  ABSTRACT  
 
The bloodstream stage of Trypanosoma brucei and probably the intracellular (amastigote) stage of Trypanosoma cruzi derive all of their energy from glycolysis. Inhibiting glycolytic enzymes may be a novel approach for the development of antitrypanosomatid drugs provided that sufficient parasite versus host selectivity can be obtained. Guided by the crystal structures of human, T. brucei, and Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase, we designed adenosine analogs as tight binding inhibitors that occupy the pocket on the enzyme that accommodates the adenosyl moiety of the NAD+ cosubstrate. Although adenosine is a very poor inhibitor, IC50 approximately 50 mM, addition of substituents to the 2' position of ribose and the N6-position of adenosine led to disubstituted nucleosides with micromolar to submicromolar potency in glyceraldehyde-3-phosphate dehydrogenase assays, an improvement of 5 orders of magnitude over the lead. The designed compounds do not inhibit the human glycolytic enzyme when tested up to their solubility limit (approximately 40 microM). When tested against cultured bloodstream T. brucei and intracellular T. cruzi, N6-(1-naphthalenemethyl)-2'-(3-chlorobenzamido)adenosine inhibited growth in the low micromolar range. Within minutes after adding this compound to bloodstream T. brucei, production of glucose-derived pyruvate ceased, parasite motility was lost, and a mixture of grossly deformed and lysed parasites was observed. These studies underscore the feasibility of using structure-based drug design to transform a mediocre lead compound into a potent enzyme inhibitor. They also suggest that energy production can be blocked in trypanosomatids with a tight binding competitive inhibitor of an enzyme in the glycolytic pathway.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Naphthalenemethyl moiety of N^6-1-naphthalenemethyladenosine modeled into the N^6-pocket of L. mexicana GAPDH. Atoms of GAPDH are shown with a doubled van der Waals surface. 		Figure 3.
Fig. 3. RASTER3D (30) model showing inhibitor 5 docked into the adenosine binding pocket of L. mexicana GAPDH. The H-bonds between N^6-H of 5 and C=O of Gln-91 and 2'-NH of 5 and CO[2]^ of Asp-38 are not drawn.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19542219 J.Frayne, A.Taylor, G.Cameron, and A.T.Hadfield (2009).
Structure of insoluble rat sperm glyceraldehyde-3-phosphate dehydrogenase (GAPDH) via heterotetramer formation with Escherichia coli GAPDH reveals target for contraceptive design.
  J Biol Chem, 284, 22703-22712.
PDB codes: 2vyn 2vyv
19445715 S.B.Roberts, J.L.Robichaux, A.K.Chavali, P.A.Manque, V.Lee, A.M.Lara, J.A.Papin, and G.A.Buck (2009).
Proteomic and network analysis characterize stage-specific metabolism in Trypanosoma cruzi.
  BMC Syst Biol, 3, 52.  
  17401215 D.Mathur, K.Anand, D.Mathur, N.Jagadish, A.Suri, and L.C.Garg (2007).
Crystallization and preliminary X-ray characterization of phosphoglucose isomerase from Mycobacterium tuberculosis H37Rv.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 353-355.  
16510976 J.L.Jenkins, and J.J.Tanner (2006).
High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase.
  Acta Crystallogr D Biol Crystallogr, 62, 290-301.
PDB codes: 1u8f 2feh
16345073 M.A.Robien, J.Bosch, F.S.Buckner, W.C.Van Voorhis, E.A.Worthey, P.Myler, C.Mehlin, E.E.Boni, O.Kalyuzhniy, L.Anderson, A.Lauricella, S.Gulde, J.R.Luft, G.DeTitta, J.M.Caruthers, K.O.Hodgson, M.Soltis, F.Zucker, C.L.Verlinde, E.A.Merritt, L.W.Schoenfeld, and W.G.Hol (2006).
Crystal structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum at 2.25 A resolution reveals intriguing extra electron density in the active site.
  Proteins, 62, 570-577.
PDB codes: 2b4r 2b4t
16101414 D.M.Lorber, and B.K.Shoichet (2005).
Hierarchical docking of databases of multiple ligand conformations.
  Curr Top Med Chem, 5, 739-749.  
16131754 J.F.Satchell, R.L.Malby, C.S.Luo, A.Adisa, A.E.Alpyurek, N.Klonis, B.J.Smith, L.Tilley, and P.M.Colman (2005).
Structure of glyceraldehyde-3-phosphate dehydrogenase from Plasmodium falciparum.
  Acta Crystallogr D Biol Crystallogr, 61, 1213-1221.
PDB code: 1ywg
15539076 J.Moyersoen, J.Choe, E.Fan, W.G.Hol, and P.A.Michels (2004).
Biogenesis of peroxisomes and glycosomes: trypanosomatid glycosome assembly is a promising new drug target.
  FEMS Microbiol Rev, 28, 603-643.  
14602444 M.P.Barrett, R.J.Burchmore, A.Stich, J.O.Lazzari, A.C.Frasch, J.J.Cazzulo, and S.Krishna (2003).
The trypanosomiases.
  Lancet, 362, 1469-1480.  
14622286 S.Ladame, M.S.Castilho, C.H.Silva, C.Denier, V.Hannaert, J.Périé, G.Oliva, and M.Willson (2003).
Crystal structure of Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase complexed with an analogue of 1,3-bisphospho-d-glyceric acid.
  Eur J Biochem, 270, 4574-4586.
PDB code: 1qxs
12023213 I.Z.Zubrzycki (2002).
Homology modeling and molecular dynamics study of NAD-dependent glycerol-3-phosphate dehydrogenase from Trypanosoma brucei rhodesiense, a potential target enzyme for anti-sleeping sickness drug development.
  Biophys J, 82, 2906-2915.  
  12445769 J.Choe, S.Suresh, G.Wisedchaisri, K.J.Kennedy, M.H.Gelb, and W.G.Hol (2002).
Anomalous differences of light elements in determining precise binding modes of ligands to glycerol-3-phosphate dehydrogenase.
  Chem Biol, 9, 1189-1197.
PDB codes: 1jdj 1m66 1m67 1n1g
  12015149 S.A.Moore, R.S.Ronimus, R.S.Roberson, and H.W.Morgan (2002).
The structure of a pyrophosphate-dependent phosphofructokinase from the Lyme disease spirochete Borrelia burgdorferi.
  Structure, 10, 659-671.
PDB code: 1kzh
11119652 A.I.Su, D.M.Lorber, G.S.Weston, W.A.Baase, B.W.Matthews, and B.K.Shoichet (2001).
Docking molecules by families to increase the diversity of hits in database screens: computational strategy and experimental evaluation.
  Proteins, 42, 279-293.  
11502531 A.M.Aronov, N.R.Munagala, I.D.Kuntz, and C.C.Wang (2001).
Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase.
  Antimicrob Agents Chemother, 45, 2571-2576.  
11512153 C.L.Verlinde, V.Hannaert, C.Blonski, M.Willson, J.J.Périé, L.A.Fothergill-Gilmore, F.R.Opperdoes, M.H.Gelb, W.G.Hol, and P.A.Michels (2001).
Glycolysis as a target for the design of new anti-trypanosome drugs.
  Drug Resist Updat, 4, 50-65.  
11405646 J.C.Bressi, C.L.Verlinde, A.M.Aronov, M.L.Shaw, S.S.Shin, L.N.Nguyen, S.Suresh, F.S.Buckner, W.C.Van Voorhis, I.D.Kuntz, W.G.Hol, and M.H.Gelb (2001).
Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design.
  J Med Chem, 44, 2080-2093.  
  11534631 J.R.Seed, and S.J.Black (2001).
The classic paper of Tobie, von Brand, and Mehlman (1950) revisited.
  J Parasitol, 87, 718-720.  
10981625 P.J.Gane, and P.M.Dean (2000).
Recent advances in structure-based rational drug design.
  Curr Opin Struct Biol, 10, 401-404.  
  10801498 S.Suresh, S.Turley, F.R.Opperdoes, P.A.Michels, and W.G.Hol (2000).
A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana.
  Structure, 8, 541-552.
PDB codes: 1evy 1evz
10468568 B.M.Bakker, M.C.Walsh, B.H.ter Kuile, F.I.Mensonides, P.A.Michels, F.R.Opperdoes, and H.V.Westerhoff (1999).
Contribution of glucose transport to the control of the glycolytic flux in Trypanosoma brucei.
  Proc Natl Acad Sci U S A, 96, 10098-10103.  
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.