PDBsum entry 1evz

Go to PDB code: 
protein ligands links
Oxidoreductase PDB id
Protein chain
346 a.a. *
Waters ×80
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of leishmania mexicana glycerol-3-phosphat dehydrogenase in complex with NAD
Structure: Glycerol-3-phosphate dehydrogenase. Chain: a. Engineered: yes
Source: Leishmania mexicana. Organism_taxid: 5665. Cellular_location: glycosome. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
2.80Å     R-factor:   0.183     R-free:   0.255
Authors: S.Suresh,S.Turley,F.R.Opperdoes,P.A.M.Michels,W.G.J.Hol
Key ref:
S.Suresh et al. (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. PubMed id: 10801498 DOI: 10.1016/S0969-2126(00)00135-0
21-Apr-00     Release date:   22-Feb-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P90551  (GPDA_LEIME) -  Glycerol-3-phosphate dehydrogenase [NAD(+)], glycosomal
366 a.a.
346 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Glycerol-3-phosphate dehydrogenase (NAD(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: sn-glycerol 3-phosphate + NAD+ = glycerone phosphate + NADH
sn-glycerol 3-phosphate
Bound ligand (Het Group name = NAD)
corresponds exactly
= glycerone phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   4 terms 
  Biological process     oxidation-reduction process   4 terms 
  Biochemical function     oxidoreductase activity     5 terms  


DOI no: 10.1016/S0969-2126(00)00135-0 Structure 8:541-552 (2000)
PubMed id: 10801498  
A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana.
S.Suresh, S.Turley, F.R.Opperdoes, P.A.Michels, W.G.Hol.
BACKGROUND: NAD-dependent glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the interconversion of dihydroxyacetone phosphate and L-glycerol-3-phosphate. Although the enzyme has been characterized and cloned from a number of sources, until now no three-dimensional structure has been determined for this enzyme. Although the utility of this enzyme as a drug target against Leishmania mexicana is yet to be established, the critical role played by GPDH in the long slender bloodstream form of the related kinetoplastid Trypanosoma brucei makes it a viable drug target against sleeping sickness. RESULTS: The 1.75 A crystal structure of apo GPDH from L. mexicana was determined by multiwavelength anomalous diffraction (MAD) techniques, and used to solve the 2.8 A holo structure in complex with NADH. Each 39 kDa subunit of the dimeric enzyme contains a 189-residue N-terminal NAD-binding domain and a 156-residue C-terminal substrate-binding domain. Significant parts of both domains share structural similarity with plant acetohydroxyacid isomeroreductase. The discovery of extra, fatty-acid like, density buried inside the C-terminal domain indicates a possible post-translational modification with an associated biological function. CONCLUSIONS: The crystal structure of GPDH from L. mexicana is the first structure of this enzyme from any source and, in view of the sequence identity of 63%, serves as a valid model for the T. brucei enzyme. The differences between the human and trypanosomal enzymes are extensive, with only 29% sequence identity between the parasite and host enzyme, and support the feasibility of exploiting the NADH-binding site to develop selective inhibitors against trypanosomal GPDH. The structure also offers a plausible explanation for the observed inhibition of the T. brucei enzyme by melarsen oxide, the active form of the trypanocidal drugs melarsoprol and cymelarsan.
  Selected figure(s)  
Figure 8.
Figure 8. Hypothetical scheme for the import of L. mexicana and other trypanosomatid GPDHs into the glycosome, mediated by Pex5, and subsequent membrane association through an aliphatic modification of a cysteine residue. It is hypothesized (see text) that prior to targeting to the glycosome, the putative aliphatic modification is enclosed in a hydrophobic pocket within the soluble protein, and once imported into the glycosome movement of a helix that caps the hydrophobic pocket would open up the pocket, exposing the aliphatic molecule and permitting membrane association.
  The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 541-552) copyright 2000.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19618917 K.Toth, T.L.Amyes, B.M.Wood, K.K.Chan, J.A.Gerlt, and J.P.Richard (2009).
An examination of the relationship between active site loop size and thermodynamic activation parameters for orotidine 5'-monophosphate decarboxylase from mesophilic and thermophilic organisms.
  Biochemistry, 48, 8006-8013.  
16650981 A.Andreeva, and A.G.Murzin (2006).
Evolution of protein fold in the presence of functional constraints.
  Curr Opin Struct Biol, 16, 399-408.  
15598351 S.Cheek, Y.Qi, S.S.Krishna, L.N.Kinch, and N.V.Grishin (2004).
4SCOPmap: automated assignment of protein structures to evolutionary superfamilies.
  BMC Bioinformatics, 5, 197.  
12913312 Y.Koga, N.Sone, S.Noguchi, and H.Morii (2003).
Transfer of pro-R hydrogen from NADH to dihydroxyacetonephosphate by sn-glycerol-1-phosphate dehydrogenase from the archaeon Methanothermobacter thermautotrophicus.
  Biosci Biotechnol Biochem, 67, 1605-1608.  
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
12196534 K.L.Kavanagh, M.Klimacek, B.Nidetzky, and D.K.Wilson (2002).
Crystal structure of Pseudomonas fluorescens mannitol 2-dehydrogenase binary and ternary complexes. Specificity and catalytic mechanism.
  J Biol Chem, 277, 43433-43442.
PDB codes: 1lj8 1m2w
12006590 K.Maithal, G.Ravindra, H.Balaram, and P.Balaram (2002).
Inhibition of plasmodium falciparum triose-phosphate isomerase by chemical modification of an interface cysteine. Electrospray ionization mass spectrometric analysis of differential cysteine reactivities.
  J Biol Chem, 277, 25106-25114.  
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.  
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.