1PZG

T.gondii LDH1 complexed with APAD and sulfate at 1.6 Angstroms


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.176 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure of Toxoplasma gondii LDH1: Active-Site Differences from Human Lactate Dehydrogenases and the Structural Basis for Efficient APAD+ Use.

Kavanagh, K.L.Elling, R.A.Wilson, D.K.

(2004) Biochemistry 43: 879-889

  • DOI: https://doi.org/10.1021/bi035108g
  • Primary Citation of Related Structures:  
    1PZE, 1PZF, 1PZG, 1PZH

  • PubMed Abstract: 

    While within a human host the opportunistic pathogen Toxoplasma gondii relies heavily on glycolysis for its energy needs. Lactate dehydrogenase (LDH), the terminal enzyme in anaerobic glycolysis necessary for NAD(+) regeneration, therefore represents an attractive therapeutic target. The tachyzoite stage lactate dehydrogenase (LDH1) from the parasite T. gondii has been crystallized in apo form and in ternary complexes containing NAD(+) or the NAD(+)-analogue 3-acetylpyridine adenine dinucleotide (APAD(+)) and sulfate or the inhibitor oxalate. Comparison of the apo and ternary models shows an active-site loop that becomes ordered upon substrate binding. This active-site loop is five residues longer than in most LDHs and necessarily adopts a different conformation. While loop isomerization is fully rate-limiting in prototypical LDHs, kinetic data suggest that LDH1's rate is limited by chemical steps. The importance of charge neutralization in ligand binding is supported by the complexes that have been crystallized as well as fluorescence quenching experiments performed with ligands at low and high pH. A methionine that replaces a serine residue and displaces an ordered water molecule often seen in LDH structures provides a structural explanation for reduced substrate inhibition. Superimposition of LDH1 with human muscle- and heart-specific LDH isoforms reveals differences in residues that line the active site that increase LDH1's hydrophobicity. These differences will aid in designing inhibitors specific for LDH1 that may be useful in treating toxoplasmic encephalitis and other complications that arise in immune-compromised individuals.


  • Organizational Affiliation

    Section of Molecular and Cellular Biology, University of California, Davis, California 95616, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
lactate dehydrogenase
A, B, C, D
331Toxoplasma gondii ME49Mutation(s): 1 
Gene Names: LDH1
EC: 1.1.1.27
UniProt
Find proteins for P90613 (Toxoplasma gondii)
Explore P90613 
Go to UniProtKB:  P90613
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP90613
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A, B, C, D
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
A3D Binding MOAD:  1PZG Ki: 2.50e+7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.176 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.935α = 90
b = 124.978β = 105.94
c = 86.388γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
phasingmodel building
CNSrefinement
PHASINGphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-02-24
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Source and taxonomy, Version format compliance
  • Version 1.3: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description