3CBK

chagasin-cathepsin B


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Displacement of the occluding loop by the parasite protein, chagasin, results in efficient inhibition of human cathepsin B.

Redzynia, I.Ljunggren, A.Abrahamson, M.Mort, J.S.Krupa, J.C.Jaskolski, M.Bujacz, G.

(2008) J Biol Chem 283: 22815-22825

  • DOI: https://doi.org/10.1074/jbc.M802064200
  • Primary Citation of Related Structures:  
    3CBJ, 3CBK

  • PubMed Abstract: 

    Cathepsin B is a papain-like cysteine protease showing both endo- and exopeptidase activity, the latter due to a unique occluding loop that restricts access to the active site cleft. To clarify the mode by which natural protein inhibitors manage to overcome this obstacle, we have analyzed the structure and function of cathepsin B in complexes with the Trypanosoma cruzi inhibitor, chagasin. Kinetic analysis revealed that substitution of His-110e, which anchors the loop in occluding position, results in 3-fold increased chagasin affinity (Ki for H110A cathepsin B, 0.35 nm) due to an improved association rate (kon, 5 x 10(5) m(-1)s(-1)). The structure of chagasin in complex with cathepsin B was solved in two crystal forms (1.8 and 2.67 angstroms resolution), demonstrating that the occluding loop is displaced to allow chagasin binding with its three loops, L4, L2, and L6, spanning the entire active site cleft. The occluding loop is differently displaced in the two structures, indicating a large range of movement and adoption of conformations forced by the inhibitor. The area of contact is slightly larger than in chagasin complexes with the endopeptidase, cathepsin L. However, residues important for high affinity to both enzymes are mainly found in the outer loops L4 and L6 of chagasin. The chagasin-cathepsin B complex provides a structural framework for modeling and design of inhibitors for cruzipain, the parasite cysteine protease and a virulence factor in Chagas disease.


  • Organizational Affiliation

    Faculty of Biotechnology and Food Sciences, Technical University of Lodz, 90-924 Lodz, Poland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin B266Homo sapiensMutation(s): 3 
Gene Names: CTSBCPSB
EC: 3.4.22.1
UniProt & NIH Common Fund Data Resources
Find proteins for P07858 (Homo sapiens)
Explore P07858 
Go to UniProtKB:  P07858
PHAROS:  P07858
GTEx:  ENSG00000164733 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07858
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Chagasin110Trypanosoma cruziMutation(s): 0 
Gene Names: cha
UniProt
Find proteins for Q966X9 (Trypanosoma cruzi)
Explore Q966X9 
Go to UniProtKB:  Q966X9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ966X9
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.066α = 90
b = 85.066β = 90
c = 115.691γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data collection
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-05-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2014-03-19
    Changes: Database references
  • Version 1.3: 2018-05-23
    Changes: Data collection
  • Version 1.4: 2021-11-10
    Changes: Database references
  • Version 1.5: 2023-11-01
    Changes: Data collection, Refinement description