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| | <StructureSection load='5c3g' size='340' side='right'caption='[[5c3g]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='5c3g' size='340' side='right'caption='[[5c3g]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5c3g]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C3G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C3G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5c3g]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5C3G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C3G FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></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=5c3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c3g OCA], [http://pdbe.org/5c3g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5c3g RCSB], [http://www.ebi.ac.uk/pdbsum/5c3g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5c3g ProSAT]</span></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=5c3g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c3g OCA], [https://pdbe.org/5c3g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c3g RCSB], [https://www.ebi.ac.uk/pdbsum/5c3g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c3g ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/B2CL1_MOUSE B2CL1_MOUSE]] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:9390687</ref> Isoform Bcl-X(S) promotes apoptosis (By similarity).<ref>PMID:9390687</ref> [[http://www.uniprot.org/uniprot/B2L11_HUMAN B2L11_HUMAN]] Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis.<ref>PMID:9430630</ref> <ref>PMID:11734221</ref> <ref>PMID:12019181</ref> <ref>PMID:11997495</ref> <ref>PMID:15147734</ref> <ref>PMID:15486195</ref> | + | [https://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Edwards, T A]] | + | [[Category: Mus musculus]] |
| - | [[Category: Miles, J A]] | + | [[Category: Edwards TA]] |
| - | [[Category: Pask, C M]] | + | [[Category: Miles JA]] |
| - | [[Category: Rodriguez-Marin, S]] | + | [[Category: Pask CM]] |
| - | [[Category: Rowell, P]] | + | [[Category: Rodriguez-Marin S]] |
| - | [[Category: Warriner, S L]] | + | [[Category: Rowell P]] |
| - | [[Category: Wilson, A J]] | + | [[Category: Warriner SL]] |
| - | [[Category: Yeo, D J]] | + | [[Category: Wilson AJ]] |
| - | [[Category: Apoptosis]]
| + | [[Category: Yeo DJ]] |
| - | [[Category: Bcl-2 family]]
| + | |
| - | [[Category: Bh3]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Stapled peptide]]
| + | |
| Structural highlights
Function
B2CL1_HUMAN Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.[1] [2] Isoform Bcl-X(S) promotes apoptosis.[3] [4]
Publication Abstract from PubMed
The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel alpha-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive alpha-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-xL and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.
Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.,Miles JA, Yeo DJ, Rowell P, Rodriguez-Marin S, Pask CM, Warriner SL, Edwards TA, Wilson AJ Chem Sci. 2016 Jun 1;7(6):3694-3702. doi: 10.1039/c5sc04048e. Epub 2016 Feb 29. PMID:28970875[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
- ↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
- ↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
- ↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
- ↑ Miles JA, Yeo DJ, Rowell P, Rodriguez-Marin S, Pask CM, Warriner SL, Edwards TA, Wilson AJ. Hydrocarbon constrained peptides - understanding preorganisation and binding affinity. Chem Sci. 2016 Jun 1;7(6):3694-3702. doi: 10.1039/c5sc04048e. Epub 2016 Feb 29. PMID:28970875 doi:http://dx.doi.org/10.1039/c5sc04048e
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