3U67

Crystal structure of the N-terminal domain of Hsp90 from Leishmania major(LmjF33.0312)in complex with ADP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.

Pizarro, J.C.Hills, T.Senisterra, G.Wernimont, A.K.Mackenzie, C.Norcross, N.R.Ferguson, M.A.Wyatt, P.G.Gilbert, I.H.Hui, R.

(2013) PLoS Negl Trop Dis 7: e2492-e2492

  • DOI: https://doi.org/10.1371/journal.pntd.0002492
  • Primary Citation of Related Structures:  
    3O6O, 3OMU, 3OPD, 3U67

  • PubMed Abstract: 

    Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.


  • Organizational Affiliation

    The Structural Genomics Consortium (SGC), University of Toronto, Toronto, Ontario, Canada ; Department of Tropical Medicine, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein 83-1231Leishmania major strain FriedlinMutation(s): 0 
Gene Names: 
UniProt
Find proteins for Q4Q4I6 (Leishmania major)
Explore Q4Q4I6 
Go to UniProtKB:  Q4Q4I6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ4Q4I6
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.865α = 90
b = 42.991β = 90
c = 51.253γ = 90
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-30
    Type: Initial release
  • Version 1.1: 2017-11-29
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description