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| | ==Crystal structure of alpha-beta-foldamer 2c in complex with Bcl-xL== | | ==Crystal structure of alpha-beta-foldamer 2c in complex with Bcl-xL== |
| - | <StructureSection load='4a1u' size='340' side='right' caption='[[4a1u]], [[Resolution|resolution]] 1.54Å' scene=''> | + | <StructureSection load='4a1u' size='340' side='right'caption='[[4a1u]], [[Resolution|resolution]] 1.54Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4a1u]] 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=4A1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A1U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4a1u]] is a 2 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=4A1U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A1U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.54Å</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=B3A:(3S)-3-AMINOBUTANOIC+ACID'>B3A</scene>, <scene name='pdbligand=B3E:(3S)-3-AMINOHEXANEDIOIC+ACID'>B3E</scene>, <scene name='pdbligand=HR7:(3S)-3-AMINO-6-[(DIAMINOMETHYLIDENE)AMINO]HEXANOIC+ACID'>HR7</scene>, <scene name='pdbligand=HT7:(3S)-3-AMINO-4-(1H-INDOL-3-YL)BUTANOIC+ACID'>HT7</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></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=B3A:(3S)-3-AMINOBUTANOIC+ACID'>B3A</scene>, <scene name='pdbligand=B3E:(3S)-3-AMINOHEXANEDIOIC+ACID'>B3E</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HR7:(3S)-3-AMINO-6-[(DIAMINOMETHYLIDENE)AMINO]HEXANOIC+ACID'>HR7</scene>, <scene name='pdbligand=HT7:(3S)-3-AMINO-4-(1H-INDOL-3-YL)BUTANOIC+ACID'>HT7</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1bxl|1bxl]], [[4a1w|4a1w]], [[1ysi|1ysi]], [[2yj1|2yj1]], [[2b48|2b48]], [[1r2e|1r2e]], [[1ysn|1ysn]], [[1ysg|1ysg]], [[1r2g|1r2g]], [[1r2h|1r2h]], [[1lxl|1lxl]], [[1r2d|1r2d]], [[1g5j|1g5j]], [[1maz|1maz]], [[1r2i|1r2i]]</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=4a1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a1u OCA], [https://pdbe.org/4a1u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a1u RCSB], [https://www.ebi.ac.uk/pdbsum/4a1u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a1u ProSAT]</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=4a1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a1u OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a1u RCSB], [http://www.ebi.ac.uk/pdbsum/4a1u PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4a1u" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Boersma, M D]] | + | [[Category: Large Structures]] |
| - | [[Category: Clarke, O B]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Colman, P M]] | + | [[Category: Boersma MD]] |
| - | [[Category: Fairlie, W D]] | + | [[Category: Clarke OB]] |
| - | [[Category: Gellman, S H]] | + | [[Category: Colman PM]] |
| - | [[Category: Haase, H S]] | + | [[Category: Fairlie WD]] |
| - | [[Category: Horne, W S]] | + | [[Category: Gellman SH]] |
| - | [[Category: Kaufman, K J]] | + | [[Category: Haase HS]] |
| - | [[Category: Lee, E F]] | + | [[Category: Horne WS]] |
| - | [[Category: Smith, B J]] | + | [[Category: Kaufman KJ]] |
| - | [[Category: Alpha-helix]] | + | [[Category: Lee EF]] |
| - | [[Category: Apoptosis]] | + | [[Category: Smith BJ]] |
| - | [[Category: Bh3]]
| + | |
| - | [[Category: Mimicry]]
| + | |
| Structural highlights
4a1u is a 2 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 1.54Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
Peptidic oligomers that contain both alpha- and beta-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of alpha-helix-forming conventional peptides (composed exclusively of alpha-amino acid residues). Here we describe a comprehensive evaluation of diverse alpha/beta-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-x(L) and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All alpha/beta-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic alpha-residue --> beta(3)-residue substitutions. Previous work has shown that the alphaalphabetaalphaalphaalphabeta pattern, which aligns the beta(3)-residues in a 'stripe' along one side of the helix, can support functional alpha-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by alphaalphabeta and alphaalphaalphabeta patterns, which cause the beta(3)-residues to spiral around the helix periphery. We find that the alphaalphaalphabeta pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an alpha/beta-peptide bound to Bcl-x(L), affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best alphaalphaalphabeta homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 alpha-peptide.
Evaluation of Diverse alpha/beta-Backbone Patterns for Functional alpha-Helix Mimicry: Analogues of the Bim BH3 Domain.,Boersma MD, Haase HS, Peterson-Kaufman KJ, Lee EF, Clarke OB, Colman PM, Smith BJ, Horne WS, Fairlie WD, Gellman SH J Am Chem Soc. 2011 Dec 8. PMID:22040025[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
- ↑ Boersma MD, Haase HS, Peterson-Kaufman KJ, Lee EF, Clarke OB, Colman PM, Smith BJ, Horne WS, Fairlie WD, Gellman SH. Evaluation of Diverse alpha/beta-Backbone Patterns for Functional alpha-Helix Mimicry: Analogues of the Bim BH3 Domain. J Am Chem Soc. 2011 Dec 8. PMID:22040025 doi:10.1021/ja207148m
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