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PDBsum entry 1u9q
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Crystal structure of cruzain bound to an alpha-ketoester
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Structure:
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Cruzipain. Chain: x. Fragment: catalytic domain. Synonym: major cysteine proteinase. Cruzaine. Engineered: yes
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Source:
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Trypanosoma cruzi. Organism_taxid: 5693. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.30Å
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R-factor:
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0.136
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R-free:
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0.218
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Authors:
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M.Lange,S.G.Weston,H.Cheng,M.Culliane,M.M.Fiorey,C.Grisostomi, L.W.Hardy,D.S.Hartstough,P.V.Pallai,R.F.Tilton,C.M.Baldino, L.S.Brinen,J.C.Engel,Y.Choe,M.S.Price,C.S.Craik
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Key ref:
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Y.Choe
et al.
(2005).
Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease.
Bioorg Med Chem Lett,
13,
2141-2156.
PubMed id:
DOI:
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Date:
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10-Aug-04
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Release date:
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29-Mar-05
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PROCHECK
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Headers
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References
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P25779
(CYSP_TRYCR) -
Cruzipain from Trypanosoma cruzi
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Seq:
Struc:
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467 a.a.
215 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
13:2141-2156
(2005)
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PubMed id:
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Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease.
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Y.Choe,
L.S.Brinen,
M.S.Price,
J.C.Engel,
M.Lange,
C.Grisostomi,
S.G.Weston,
P.V.Pallai,
H.Cheng,
L.W.Hardy,
D.S.Hartsough,
M.McMakin,
R.F.Tilton,
C.M.Baldino,
C.S.Craik.
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ABSTRACT
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Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas
disease, a major cause of cardiovascular disease in many Latin American
countries. There is an urgent need to develop an improved therapy due to the
toxicity of existing drugs and emerging drug resistance. Cruzain, the primary
cysteine protease of T. cruzi, is essential for the survival of the parasite in
host cells and therefore is an important target for the development of
inhibitors as potential therapeutics. A novel series of alpha-ketoamide-,
alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has
been developed. The inhibitors were identified by screening protease targeted
small molecule libraries and systematically optimizing the P1, P2, P3, and P1'
residues using specific structure-guided methods. A total of 20 compounds
displayed picomolar potency in in vitro assays and three inhibitors representing
different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal
activity in cell culture. A 2.3A crystallographic structure of cruzain bound
with one of the alpha-ketoester analogs is also reported. The structure and
kinetic assay data illustrate the covalent binding, reversible inhibition
mechanism of the inhibitor. Information on the compounds reported here will be
useful in the development of new lead compounds as potential therapeutic agents
for the treatment of Chagas disease and as biological probes to study the role
that cruzain plays in the pathology. This study also demonstrates the validity
of structure-guided approaches to focused library design and lead compound
optimization.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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H.C.Castro,
P.A.Abreu,
R.B.Geraldo,
R.C.Martins,
R.Dos Santos,
N.I.Loureiro,
L.M.Cabral,
and
C.R.Rodrigues
(2011).
Looking at the proteases from a simple perspective.
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J Mol Recognit,
24,
165-181.
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G.G.Xu,
and
F.A.Etzkorn
(2010).
Convergent synthesis of alpha-ketoamide inhibitors of Pin1.
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Org Lett,
12,
696-699.
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K.Steert,
M.Berg,
J.C.Mottram,
G.D.Westrop,
G.H.Coombs,
P.Cos,
L.Maes,
J.Joossens,
P.Van der Veken,
A.Haemers,
and
K.Augustyns
(2010).
α-ketoheterocycles as inhibitors of Leishmania mexicana cysteine protease CPB.
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ChemMedChem,
5,
1734-1748.
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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.
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PLoS Negl Trop Dis,
4,
0.
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PDB code:
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D.Castro,
L.Boiani,
D.Benitez,
P.Hernández,
A.Merlino,
C.Gil,
C.Olea-Azar,
M.González,
H.Cerecetto,
and
W.Porcal
(2009).
Anti-trypanosomatid benzofuroxans and deoxygenated analogues: synthesis using polymer-supported triphenylphosphine, biological evaluation and mechanism of action studies.
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Eur J Med Chem,
44,
5055-5065.
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M.N.Soeiro,
and
S.L.de Castro
(2009).
Trypanosoma cruzi targets for new chemotherapeutic approaches.
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Expert Opin Ther Targets,
13,
105-121.
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Z.Yang,
M.Fonović,
S.H.Verhelst,
G.Blum,
and
M.Bogyo
(2009).
Evaluation of alpha,beta-unsaturated ketone-based probes for papain-family cysteine proteases.
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Bioorg Med Chem,
17,
1071-1078.
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A.C.Leite,
D.R.de M Moreira,
M.V.de O Cardoso,
M.Z.Hernandes,
V.R.Alves Pereira,
R.O.Silva,
A.C.Kiperstok,
M.da S Lima,
and
M.B.Soares
(2007).
Synthesis, Cruzain Docking, and in vitro Studies of Aryl-4-Oxothiazolylhydrazones Against Trypanosoma cruzi.
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ChemMedChem,
2,
1339-1345.
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F.C.Reis,
T.F.Costa,
T.Sulea,
A.Mezzetti,
J.Scharfstein,
D.Brömme,
R.Ménard,
and
A.P.Lima
(2007).
The propeptide of cruzipain--a potent selective inhibitor of the trypanosomal enzymes cruzipain and brucipain, and of the human enzyme cathepsin F.
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FEBS J,
274,
1224-1234.
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A.C.Leite,
R.S.de Lima,
D.R.Moreira,
M.V.Cardoso,
A.C.Gouveia de Brito,
L.M.Farias Dos Santos,
M.Z.Hernandes,
A.C.Kiperstok,
R.S.de Lima,
and
M.B.Soares
(2006).
Synthesis, docking, and in vitro activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acyl-thiazolidones against Trypanosoma cruzi.
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Bioorg Med Chem,
14,
3749-3757.
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R.Dey,
J.Bhattacharya,
and
S.C.Datta
(2006).
Calcium-dependent proteolytic activity of a cysteine protease caldonopain is detected during Leishmania infection.
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Mol Cell Biochem,
281,
27-33.
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T.Hogg,
K.Nagarajan,
S.Herzberg,
L.Chen,
X.Shen,
H.Jiang,
M.Wecke,
C.Blohmke,
R.Hilgenfeld,
and
C.L.Schmidt
(2006).
Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum.
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J Biol Chem,
281,
25425-25437.
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PDB code:
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A.Zick,
I.Onn,
R.Bezalel,
H.Margalit,
and
J.Shlomai
(2005).
Assigning functions to genes: identification of S-phase expressed genes in Leishmania major based on post-transcriptional control elements.
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Nucleic Acids Res,
33,
4235-4242.
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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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Links
