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PDBsum entry 3i06
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Hydrolase PDB id
3i06

 

 

 

 

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Contents
Protein chain
215 a.a. *
Ligands
QL2
Waters ×338
* Residue conservation analysis
PDB id:
3i06
Name: Hydrolase
Title: Crystal structure of cruzain covalently bound to a purine nitrile
Structure: Cruzipain. Chain: a. Fragment: resudues 123-337. Synonym: cruzaine, major cysteine proteinase. Engineered: yes
Source: Trypanosoma cruzi. Organism_taxid: 5693. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.10Å     R-factor:   0.120     R-free:   0.142
Authors: R.S.Ferreira,B.K.Shoichet,J.H.Mckerrow
Key ref: B.T.Mott et al. (2010). Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB. J Med Chem, 53, 52-60. PubMed id: 19908842
Date:
24-Jun-09     Release date:   15-Dec-09    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P25779  (CYSP_TRYCR) -  Cruzipain from Trypanosoma cruzi
Seq:
Struc: 		467 a.a.
215 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.22.51  - cruzipain.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
J Med Chem 53:52-60 (2010)
PubMed id: 19908842  
 
 
Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
B.T.Mott, R.S.Ferreira, A.Simeonov, A.Jadhav, K.K.Ang, W.Leister, M.Shen, J.T.Silveira, P.S.Doyle, M.R.Arkin, J.H.McKerrow, J.Inglese, C.P.Austin, C.J.Thomas, B.K.Shoichet, D.J.Maloney.
 
  ABSTRACT  
 
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20426472 A.K.Doak, H.Wille, S.B.Prusiner, and B.K.Shoichet (2010).
Colloid formation by drugs in simulated intestinal fluid.
  J Med Chem, 53, 4259-4265.  
20229566 M.B.Boxer, A.M.Quinn, M.Shen, A.Jadhav, W.Leister, A.Simeonov, D.S.Auld, and C.J.Thomas (2010).
A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety.
  ChemMedChem, 5, 730-738.  
20540517 R.S.Ferreira, A.Simeonov, A.Jadhav, O.Eidam, B.T.Mott, M.J.Keiser, J.H.McKerrow, D.J.Maloney, J.J.Irwin, and B.K.Shoichet (2010).
Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
  J Med Chem, 53, 4891-4905.
PDB code: 3kku
  20856868 Y.T.Chen, L.S.Brinen, I.D.Kerr, E.Hansell, P.S.Doyle, J.H.McKerrow, and W.R.Roush (2010).
In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.
  PLoS Negl Trop Dis, 4, 0.
PDB code: 3lxs
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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