2c2m

From Proteopedia

(Difference between revisions)

Current revision

Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.

Structural highlights

2c2m is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.94Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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.

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^[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
↑ Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grutter MG, Powers JC. Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10. J Med Chem. 2006 Sep 21;49(19):5728-49. PMID:16970398 doi:http://dx.doi.org/10.1021/jm0601405

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/2c2m"

@@ Line 1: / Line 1: @@
-[[Image:2c2m.gif|left|200px]]<br />
-<applet load="2c2m" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2c2m, resolution 1.94&Aring;" />
-'''CRYSTAL STRUCTURES OF CASPASE-3 IN COMPLEX WITH AZA-PEPTIDE MICHAEL ACCEPTOR INHIBITORS.'''<br />
-==Overview==
+==Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.==
-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.
+<StructureSection load='2c2m' size='340' side='right'caption='[[2c2m]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2c2m]] 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=2C2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C2M 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]] 1.94&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MX4:{1-[4-(BENZYLOXY)-4-OXOBUTANOYL]HYDRAZINO}ACETIC+ACID'>MX4</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=2c2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2m OCA], [https://pdbe.org/2c2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c2m RCSB], [https://www.ebi.ac.uk/pdbsum/2c2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c2m 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/c2/2c2m_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=2c2m 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.
-==About this Structure==
+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>
-C2M is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2C2M OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16970398 16970398]
+</div>
-[[Category: Homo sapiens]]
+<div class="pdbe-citations 2c2m" style="background-color:#fffaf0;"></div>
-[[Category: Protein complex]]
-[[Category: Asgian, J.L.]]
-[[Category: Campbell, A.J.]]
-[[Category: Ekici, O.D.]]
-[[Category: Ganesan, R.]]
-[[Category: Gruetter, M.G.]]
-[[Category: James, K.E.]]
-[[Category: Jelakovic, S.]]
-[[Category: Li, Z.Z.]]
-[[Category: Mikolajczyk, J.]]
-[[Category: Powers, J.C.]]
-[[Category: Salvesen, G.S.]]
-[[Category: apoptosis]]
-[[Category: aza-asp]]
-[[Category: aza-peptide]]
-[[Category: clan cd]]
-[[Category: complex (protease-inhibitor)]]
-[[Category: cpp32]]
-[[Category: cysteine-protease]]
-[[Category: hydrolase]]
-[[Category: ice]]
-[[Category: michael acceptor]]
-[[Category: tetramer]]
-[[Category: thiol protease]]
-[[Category: yama]]
-[[Category: zymogen]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:09:52 2007''
+==See Also==
+*[[Caspase 3D structures|Caspase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Synthetic construct]]
+[[Category: Asgian JL]]
+[[Category: Campbell A]]
+[[Category: Ekici OD]]
+[[Category: Ganesan R]]
+[[Category: Gruetter MG]]
+[[Category: James KE]]
+[[Category: Jelakovic S]]
+[[Category: Li ZZ]]
+[[Category: Mikolajczyk J]]
+[[Category: Powers JC]]
+[[Category: Salvesen GS]]

2c2m

From Proteopedia

Current revision

Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor 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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