1u9q

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{{STRUCTURE_1u9q| PDB=1u9q | SCENE= }}
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==Crystal structure of cruzain bound to an alpha-ketoester==
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===Crystal structure of cruzain bound to an alpha-ketoester===
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<StructureSection load='1u9q' size='340' side='right' caption='[[1u9q]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_15727867}}
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== Structural highlights ==
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<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>
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</td></tr><tr><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><br>
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<tr><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>
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<tr><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>
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<tr><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>
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<table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u9/1u9q_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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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==Function==
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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<ref>PMID:15727867</ref>
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[[http://www.uniprot.org/uniprot/CYSP_TRYCR 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.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[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].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:015727867</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Cruzipain]]
[[Category: Cruzipain]]
[[Category: Trypanosoma cruzi]]
[[Category: Trypanosoma cruzi]]

Revision as of 11:46, 3 October 2014

Crystal structure of cruzain bound to an alpha-ketoester

1u9q, resolution 2.30Å

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