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1u9q

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Revision as of 21:59, 10 September 2015

Crystal structure of cruzain bound to an alpha-ketoester

Structural highlights

1u9q is a 1 chain structure with sequence from Trycr. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1f2a, 1f29, 1f2b, 1f2c, 1me3, 1me4
Activity:	Cruzipain, with EC number 3.4.22.51
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[CYSP_TRYCR] Hydrolyzes chromogenic peptides at the carboxyl Arg or Lys; requires at least one more amino acid, preferably Arg, Phe, Val or Leu, between the terminal Arg or Lys and the amino-blocking group. The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease.,Choe Y, Brinen LS, Price MS, Engel JC, Lange M, Grisostomi C, Weston SG, Pallai PV, Cheng H, Hardy LW, Hartsough DS, McMakin M, Tilton RF, Baldino CM, Craik CS Bioorg Med Chem. 2005 Mar 15;13(6):2141-56. PMID:15727867^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Choe Y, Brinen LS, Price MS, Engel JC, Lange M, Grisostomi C, Weston SG, Pallai PV, Cheng H, Hardy LW, Hartsough DS, McMakin M, Tilton RF, Baldino CM, Craik CS. Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Bioorg Med Chem. 2005 Mar 15;13(6):2141-56. PMID:15727867 doi:10.1016/j.bmc.2004.12.053

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1u9q"

@@ Line 2: / Line 2: @@
 <StructureSection load='1u9q' size='340' side='right' caption='[[1u9q]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1u9q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U9Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1U9Q FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1u9q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U9Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1U9Q FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=186:[1-(1-METHYL-4,5-DIOXO-PENT-2-ENYLCARBAMOYL)-2-PHENYL-ETHYL]-CARBAMIC+ACID+BENZYL+ESTER'>186</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1f2a|1f2a]], [[1f29|1f29]], [[1f2b|1f2b]], [[1f2c|1f2c]], [[1me3|1me3]], [[1me4|1me4]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cruzipain Cruzipain], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.51 3.4.22.51] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1u9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u9q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1u9q RCSB], [http://www.ebi.ac.uk/pdbsum/1u9q PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1u9q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u9q OCA], [http://pdbe.org/1u9q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1u9q RCSB], [http://www.ebi.ac.uk/pdbsum/1u9q PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 28: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1u9q" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 33: / Line 34: @@
 </StructureSection>
 [[Category: Cruzipain]]
-[[Category: Trypanosoma cruzi]]
+[[Category: Trycr]]
 [[Category: Baldino, C M]]
 [[Category: Brinen, L S]]

1u9q

From Proteopedia

Revision as of 21:59, 10 September 2015

Crystal structure of cruzain bound to an alpha-ketoester

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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