4IU1

Crystal structure of Leishmania mexicana arginase in complex with inhibitor nor-NOHA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.142 
  • R-Value Observed: 0.142 

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This is version 1.3 of the entry. See complete history


Literature

Crystal structure of arginase from Leishmania mexicana and implications for the inhibition of polyamine biosynthesis in parasitic infections.

D'Antonio, E.L.Ullman, B.Roberts, S.C.Dixit, U.G.Wilson, M.E.Hai, Y.Christianson, D.W.

(2013) Arch Biochem Biophys 535: 163-176

  • DOI: https://doi.org/10.1016/j.abb.2013.03.015
  • Primary Citation of Related Structures:  
    4ITY, 4IU0, 4IU1, 4IU4, 4IU5

  • PubMed Abstract: 

    Arginase from parasitic protozoa belonging to the genus Leishmania is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme catalyzes the first committed step in the biosynthesis of polyamines that enable cell growth and survival. The high resolution X-ray crystal structures of the unliganded form of Leishmania mexicana arginase (LmARG) and four inhibitor complexes are now reported. These complexes include the reactive substrate analogue 2(S)-amino-6-boronohexanoic acid (ABH) and the hydroxylated substrate analogue nor-N(ω)-hydroxy-l-arginine (nor-NOHA), which are the most potent arginase inhibitors known to date. Comparisons of the LmARG structure with that of the archetypal arginase, human arginase I, reveal that all residues important for substrate binding and catalysis are strictly conserved. However, three regions of tertiary structure differ between the parasitic enzyme and the human enzyme corresponding to the G62 - S71, L161 - C172, and I219 - V230 segments of LmARG. Additionally, variations are observed in salt link interactions that stabilize trimer assembly in LmARG. We also report biological studies in which we demonstrate that localization of LmARG to the glycosome, a unique subcellular organelle peculiar to Leishmania and related parasites, is essential for robust pathogenesis.


  • Organizational Affiliation

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Arginase330Leishmania mexicanaMutation(s): 0 
Gene Names: ARG
EC: 3.5.3.1
UniProt
Find proteins for Q6TUJ5 (Leishmania mexicana)
Explore Q6TUJ5 
Go to UniProtKB:  Q6TUJ5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6TUJ5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
NNH PDBBind:  4IU1 Ki: 5.00e+4 (nM) from 1 assay(s)
Binding MOAD:  4IU1 Ki: 5.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.142 
  • R-Value Observed: 0.142 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.615α = 90
b = 89.615β = 90
c = 114.556γ = 120
Software Package:
Software NamePurpose
CBASSdata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-30
    Type: Initial release
  • Version 1.1: 2013-05-01
    Changes: Database references
  • Version 1.2: 2013-05-22
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description