1nms: Difference between revisions

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-[[Image:1nms.gif|left|200px]]
- {{Structure
+==Caspase-3 tethered to irreversible inhibitor==
-|PDB= 1nms |SIZE=350|CAPTION= <scene name='initialview01'>1nms</scene>, resolution 1.70&Aring;
+<StructureSection load='1nms' size='340' side='right'caption='[[1nms]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
-|SITE=
+== Structural highlights ==
-|LIGAND= <scene name='pdbligand=161:5-[4-(1-CARBOXYMETHYL-2-OXO-PROPYLCARBAMOYL)-BENZYLSULFAMOYL]-2-HYDROXY-BENZOIC+ACID'>161</scene>
+<table><tr><td colspan='2'>[[1nms]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NMS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NMS FirstGlance]. <br>
-|ACTIVITY=
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
-|GENE=
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=161:5-[4-(1-CARBOXYMETHYL-2-OXO-PROPYLCARBAMOYL)-BENZYLSULFAMOYL]-2-HYDROXY-BENZOIC+ACID'>161</scene></td></tr>
-|DOMAIN=
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1nms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nms OCA], [https://pdbe.org/1nms PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nms RCSB], [https://www.ebi.ac.uk/pdbsum/1nms PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nms ProSAT]</span></td></tr>
-|RELATEDENTRY=[[1nme|1NME]], [[1nmq|1NMQ]]
+</table>
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1nms FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nms OCA], [http://www.ebi.ac.uk/pdbsum/1nms PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1nms RCSB]</span>
+== 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/nm/1nms_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1nms ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
-'''Caspase-3 tethered to irreversible inhibitor'''
+In situ assembly of enzyme inhibitors using extended tethering.,Erlanson DA, Lam JW, Wiesmann C, Luong TN, Simmons RL, DeLano WL, Choong IC, Burdett MT, Flanagan WM, Lee D, Gordon EM, O'Brien T Nat Biotechnol. 2003 Mar;21(3):308-14. Epub 2003 Feb 3. PMID:12563278<ref>PMID:12563278</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 1nms" style="background-color:#fffaf0;"></div>
-==Overview==
+==See Also==
-Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
+*[[Caspase 3D structures|Caspase 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-NMS is a [[Single protein]] structure of 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=1NMS OCA].
+__TOC__
+</StructureSection>
-==Reference==
-In situ assembly of enzyme inhibitors using extended tethering., Erlanson DA, Lam JW, Wiesmann C, Luong TN, Simmons RL, DeLano WL, Choong IC, Burdett MT, Flanagan WM, Lee D, Gordon EM, O'Brien T, Nat Biotechnol. 2003 Mar;21(3):308-14. Epub 2003 Feb 3. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12563278 12563278]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Brian, T O.]]
+[[Category: Choong IC]]
-[[Category: Choong, I C.]]
+[[Category: DeLano WL]]
-[[Category: DeLano, W L.]]
+[[Category: Erlanson DA]]
-[[Category: Erlanson, D A.]]
+[[Category: Flanagan WM]]
-[[Category: Flanagan, W M.]]
+[[Category: Lam J]]
-[[Category: Lam, J.]]
+[[Category: Lee D]]
-[[Category: Lee, D.]]
+[[Category: Luong TN]]
-[[Category: Luong, T N.]]
+[[Category: O'Brian T]]
-[[Category: Simmons, R L.]]
+[[Category: Simmons RL]]
-[[Category: Wiesmann, C.]]
+[[Category: Wiesmann C]]
-[[Category: caspase-3]]
-[[Category: inhibitor]]
-[[Category: irreversible]]
-[[Category: tether]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:32:32 2008''