1LF3

CRYSTAL STRUCTURE OF PLASMEPSIN II FROM P FALCIPARUM IN COMPLEX WITH INHIBITOR EH58


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.

Asojo, O.A.Gulnik, S.V.Afonina, E.Yu, B.Ellman, J.A.Haque, T.S.Silva, A.M.

(2003) J Mol Biol 327: 173-181

  • DOI: https://doi.org/10.1016/s0022-2836(03)00036-6
  • Primary Citation of Related Structures:  
    1LF3, 1LF4, 1LS5

  • PubMed Abstract: 

    Malaria remains a human disease of global significance and a major cause of high infant mortality in endemic nations. Parasites of the genus Plasmodium cause the disease by degrading human hemoglobin as a source of amino acids for their growth and maturation. Hemoglobin degradation is initiated by aspartic proteases, termed plasmepsins, with a cleavage at the alpha-chain between residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active plasmepsins that has been identified in the food vacuole of Plasmodium falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the complex with a potent inhibitor have been refined with data extending to resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%, respectively. The inhibitor, N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dimethoxy-benzamide, belongs to a family of potent non-peptidic inhibitors that have large P1' groups. Such inhibitors could not be modeled into the binding cavity of the structure of plasmepsin II in complex with pepstatin A. Our structures reveal that the binding cavities of the new complex and uncomplexed plasmepsin II are considerably more open than that of the pepstatin A complex, allowing for larger heterocyclic groups in the P1', P2' and P2 positions. Both complexed and uncomplexed plasmepsin II crystallized in space group P2, with one monomer in the asymmetric unit. The structures show extensive interlocking of monomers around the crystallographic axis of symmetry, with areas in excess of 2300A(2) buried at the interface, and a loop of one monomer interacting with the binding cavity of the 2-fold related monomer. Electron density for this loop is only fully ordered in the complexed structure.


  • Organizational Affiliation

    Structural Biochemistry Program, National Cancer Institute/SAIC, Frederick, MD 21702, USA. asojo@ncifcrf.gov


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
plasmepsin 2331Plasmodium falciparumMutation(s): 0 
EC: 3.4.23.39
UniProt
Find proteins for P46925 (Plasmodium falciparum (isolate HB3))
Explore P46925 
Go to UniProtKB:  P46925
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP46925
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EH5
Query on EH5

Download Ideal Coordinates CCD File 
B [auth A]N-(1-BENZYL-3-{[3-(1,3-DIOXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PROPIONYL]-[2-(HEXAHYDRO-BENZO[1,3]DIOXOL-5-YL)-ETHYL]-AMINO}-2-HYDROXY-PROPYL)-4-BENZYLOXY-3,5-DIMETHOXY-BENZAMIDE
C46 H51 N3 O10
PJQGNNQTZMYXOB-HAMMGQCISA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EH5 PDBBind:  1LF3 Ki: 100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.178 
  • Space Group: P 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.411α = 90
b = 39.904β = 105.11
c = 91.409γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2002-10-10
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description