3IUT

The Crystal Structure of Cruzain in Complex with a Tetrafluorophenoxymethyl Ketone Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.153 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy.

Brak, K.Kerr, I.D.Barrett, K.T.Fuchi, N.Debnath, M.Ang, K.Engel, J.C.McKerrow, J.H.Doyle, P.S.Brinen, L.S.Ellman, J.A.

(2010) J Med Chem 53: 1763-1773

  • DOI: https://doi.org/10.1021/jm901633v
  • Primary Citation of Related Structures:  
    3IUT

  • PubMed Abstract: 

    A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.


  • Organizational Affiliation

    Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cruzipain221Trypanosoma cruziMutation(s): 2 
Gene Names: cruzipain
EC: 3.4.22.51
UniProt
Find proteins for P25779 (Trypanosoma cruzi)
Explore P25779 
Go to UniProtKB:  P25779
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25779
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
KB2 PDBBind:  3IUT Ki: 460 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.153 
  • R-Value Work: 0.127 
  • R-Value Observed: 0.128 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.081α = 90
b = 51.451β = 115.5
c = 45.853γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2021-10-13
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-09-06
    Changes: Data collection, Refinement description