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1nmq

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Revision as of 19:58, 25 December 2014

Extendend Tethering: In Situ Assembly of Inhibitors

Structural highlights

1nmq is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1nme, 1nms
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[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.^[1] ^[2]

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

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.

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^[3]

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

References

↑ Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:http://dx.doi.org/10.1038/376037a0
↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
↑ 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. In situ assembly of enzyme inhibitors using extended tethering. Nat Biotechnol. 2003 Mar;21(3):308-14. Epub 2003 Feb 3. PMID:12563278 doi:10.1038/nbt786

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1nmq]] is a 2 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=1NMQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1NMQ FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=160:3-(3-{2-[(5-METHANESULFONYL-THIOPHENE-2-CARBONYL)-AMINO]-ETHYLDISULFANYLMETHYL}-+BENZENESULFONYLAMINO)-4-OXO-PENTANOIC+ACID'>160</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=160:3-(3-{2-[(5-METHANESULFONYL-THIOPHENE-2-CARBONYL)-AMINO]-ETHYLDISULFANYLMETHYL}-+BENZENESULFONYLAMINO)-4-OXO-PENTANOIC+ACID'>160</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nme|1nme]], [[1nms|1nms]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nme|1nme]], [[1nms|1nms]]</td></tr>
-<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=1nmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nmq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1nmq RCSB], [http://www.ebi.ac.uk/pdbsum/1nmq 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=1nmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nmq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1nmq RCSB], [http://www.ebi.ac.uk/pdbsum/1nmq PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://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]]
@@ Line 33: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Brian, T O.]]
+[[Category: Brian, T O]]
-[[Category: Choong, I C.]]
+[[Category: Choong, I C]]
-[[Category: DeLano, W.]]
+[[Category: DeLano, W]]
-[[Category: Erlanson, D A.]]
+[[Category: Erlanson, D A]]
-[[Category: Flanagan, M.]]
+[[Category: Flanagan, M]]
-[[Category: Lam, J.]]
+[[Category: Lam, J]]
-[[Category: Lee, D.]]
+[[Category: Lee, D]]
-[[Category: Luong, T N.]]
+[[Category: Luong, T N]]
-[[Category: Simmons, R L.]]
+[[Category: Simmons, R L]]
-[[Category: Wiesmann, C.]]
+[[Category: Wiesmann, C]]
 [[Category: Apoptosis]]
 [[Category: Caspase-3]]

1nmq

From Proteopedia

Revision as of 19:58, 25 December 2014

Extendend Tethering: In Situ Assembly of Inhibitors

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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