1nms: Difference between revisions

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~~{{Seed}}~~

~~[[Image:1nms.png|left|200px]]~~

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==Caspase-3 tethered to irreversible inhibitor==

~~The line below this paragraph, containing~~ "~~STRUCTURE_1nms~~"~~, creates the~~ "~~Structure Box~~" on the ~~page~~.

~~You may change~~ the ~~PDB parameter~~ (~~which sets the PDB file loaded into the applet~~)

== Structural highlights ==

~~or the SCENE parameter~~ (~~which sets~~ the ~~initial scene displayed when~~ the ~~page is loaded)~~,

<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>

~~or leave~~ the ~~SCENE parameter empty for~~ the ~~default display~~.

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr>

-->

<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>

~~{{STRUCTURE_1nms| PDB~~=~~1nms | SCENE~~= }}

<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>

</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>

<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].

== 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®/PubMed®, a database of the U.S. National Library of Medicine.<br>

</div>

~~<!--~~

==See Also==

~~The line below this paragraph, {{ABSTRACT_PUBMED_12563278}}, adds the Publication Abstract to the page~~

*[[Caspase 3D structures|Caspase 3D structures]]

~~(as it appears on PubMed at http://www.pubmed.gov), where 12563278 is the PubMed ID number.~~

== References ==

~~-->~~

~~{{ABSTRACT_PUBMED_12563278}}~~

__TOC__

</StructureSection>

==~~About this Structure~~==

~~1NMS is a 2 chains structure of sequences 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~~].

==~~Reference~~==

<~~ref group="xtra">PMID:12563278<~~/~~ref~~><~~references group="xtra"~~/>

[[Category: Homo sapiens]]

[[Category: ~~Brian, T O.~~]]

[[Category: Large Structures]]

[[Category: Choong~~, I C.~~]]

[[Category: Choong IC]]

[[Category: DeLano~~, W L.~~]]

[[Category: DeLano WL]]

[[Category: Erlanson~~, D A.~~]]

[[Category: Erlanson DA]]

[[Category: Flanagan~~, W M.~~]]

[[Category: Flanagan WM]]

[[Category: Lam, J.]]

[[Category: Lam J]]

[[Category: Lee, D.]]

[[Category: Lee D]]

[[Category: Luong~~, T N.~~]]

[[Category: Luong TN]]

[[Category: ~~Simmons, R L.~~]]

[[Category: O'Brian T]]

[[Category: ~~Wiesmann, C.~~]]

[[Category: Simmons RL]]

[[Category: ~~Caspase-3]]~~

[[Category: Wiesmann C]]

~~[[Category: Inhibitor]]~~

~~[[Category: Irreversible]]~~

~~[[Category: Tether~~]]

~~''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 17:15:14 2009''~~

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@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:1nms.png|left|200px]]
-<!--
+==Caspase-3 tethered to irreversible inhibitor==
-The line below this paragraph, containing "STRUCTURE_1nms", creates the "Structure Box" on the page.
+<StructureSection load='1nms' size='340' side='right'caption='[[1nms]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<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>
-or leave the SCENE parameter empty for the default display.
+</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>
--->
+<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>
-{{STRUCTURE_1nms|  PDB=1nms  |  SCENE=  }}
+<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>
+</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/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>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_12563278}}, adds the Publication Abstract to the page
+*[[Caspase 3D structures|Caspase 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 12563278 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_12563278}}
+__TOC__
+</StructureSection>
-==About this Structure==
-NMS is a 2 chains structure of sequences 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].
-==Reference==
-<ref group="xtra">PMID:12563278</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Brian, T O.]]
+[[Category: Large Structures]]
-[[Category: Choong, I C.]]
+[[Category: Choong IC]]
-[[Category: DeLano, W L.]]
+[[Category: DeLano WL]]
-[[Category: Erlanson, D A.]]
+[[Category: Erlanson DA]]
-[[Category: Flanagan, W M.]]
+[[Category: Flanagan WM]]
-[[Category: Lam, J.]]
+[[Category: Lam J]]
-[[Category: Lee, D.]]
+[[Category: Lee D]]
-[[Category: Luong, T N.]]
+[[Category: Luong TN]]
-[[Category: Simmons, R L.]]
+[[Category: O'Brian T]]
-[[Category: Wiesmann, C.]]
+[[Category: Simmons RL]]
-[[Category: Caspase-3]]
+[[Category: Wiesmann C]]
-[[Category: Inhibitor]]
-[[Category: Irreversible]]
-[[Category: Tether]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 17:15:14 2009''