2c1e: Difference between revisions

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-[[Image:2c1e.png|left|200px]]
-{{STRUCTURE_2c1e|  PDB=2c1e  |  SCENE=  }}
+==Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.==
+<StructureSection load='2c1e' size='340' side='right'caption='[[2c1e]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2c1e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C1E FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.77&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AA1:[1-(4-ETHOXY-4-OXOBUTANOYL)HYDRAZINO]ACETIC+ACID'>AA1</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2c1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c1e OCA], [https://pdbe.org/2c1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c1e RCSB], [https://www.ebi.ac.uk/pdbsum/2c1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c1e ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CASP3_HUMAN CASP3_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.<ref>PMID:7596430</ref> <ref>PMID:21357690</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c1/2c1e_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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/main_output.php?pdb_ID=2c1e ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Aza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1' moiety.
-===Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.===
+Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10.,Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grutter MG, Powers JC J Med Chem. 2006 Sep 21;49(19):5728-49. PMID:16970398<ref>PMID:16970398</ref>
-{{ABSTRACT_PUBMED_16970398}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 2c1e" style="background-color:#fffaf0;"></div>
-[[2c1e]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C1E OCA].
 ==See Also==
-*[[Caspase|Caspase]]
+*[[Caspase 3D structures|Caspase 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:016970398</ref><ref group="xtra">PMID:019465933</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Grutter, M G.]]
+[[Category: Large Structures]]
-[[Category: Apoptosis]]
+[[Category: Synthetic construct]]
-[[Category: Aza-asp]]
+[[Category: Grutter MG]]
-[[Category: Aza-peptide]]
-[[Category: Clan cd]]
-[[Category: Cpp32]]
-[[Category: Cysteine-protease]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Michael acceptor]]
-[[Category: Thiol protease]]
-[[Category: Yama]]
-[[Category: Zymogen]]