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| | ==MCL-1 complex with MCL-1-specific selected peptide== | | ==MCL-1 complex with MCL-1-specific selected peptide== |
| - | <StructureSection load='3kz0' size='340' side='right' caption='[[3kz0]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='3kz0' size='340' side='right'caption='[[3kz0]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3kz0]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KZ0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3kz0]] is a 4 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=3KZ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KZ0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.349Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2L3, MCL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=3kz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kz0 OCA], [http://pdbe.org/3kz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kz0 RCSB], [http://www.ebi.ac.uk/pdbsum/3kz0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3kz0 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=3kz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kz0 OCA], [https://pdbe.org/3kz0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kz0 RCSB], [https://www.ebi.ac.uk/pdbsum/3kz0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kz0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref> | + | [https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kz/3kz0_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kz/3kz0_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3kz0" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3kz0" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Dutta, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Fire, E]] | + | [[Category: Dutta S]] |
| - | [[Category: Grant, R A]] | + | [[Category: Fire E]] |
| - | [[Category: Keating, A E]]
| + | [[Category: Grant RA]] |
| - | [[Category: Sauer, R T]] | + | [[Category: Keating AE]] |
| - | [[Category: Anti-apoptotic]] | + | [[Category: Sauer RT]] |
| - | [[Category: Apoptosis]] | + | |
| - | [[Category: Bcl-2]]
| + | |
| - | [[Category: Bh3]]
| + | |
| - | [[Category: Mitochondrion]]
| + | |
| Structural highlights
Function
MCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1]
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
Interactions among Bcl-2 family proteins are important for regulating apoptosis. Prosurvival members of the family interact with proapoptotic BH3 (Bcl-2-homology-3)-only members, inhibiting execution of cell death through the mitochondrial pathway. Structurally, this interaction is mediated by binding of the alpha-helical BH3 region of the proapoptotic proteins to a conserved hydrophobic groove on the prosurvival proteins. Native BH3-only proteins exhibit selectivity in binding prosurvival members, as do small molecules that block these interactions. Understanding the sequence and structural basis of interaction specificity in this family is important, as it may allow the prediction of new Bcl-2 family associations and/or the design of new classes of selective inhibitors to serve as reagents or therapeutics. In this work, we used two complementary techniques--yeast surface display screening from combinatorial peptide libraries and SPOT peptide array analysis--to elucidate specificity determinants for binding to Bcl-x(L)versus Mcl-1, two prominent prosurvival proteins. We screened a randomized library and identified BH3 peptides that bound to either Mcl-1 or Bcl-x(L) selectively or to both with high affinity. The peptides competed with native ligands for binding into the conserved hydrophobic groove, as illustrated in detail by a crystal structure of a specific peptide bound to Mcl-1. Mcl-1-selective peptides from the screen were highly specific for binding Mcl-1 in preference to Bcl-x(L), Bcl-2, Bcl-w, and Bfl-1, whereas Bcl-x(L)-selective peptides showed some cross-interaction with related proteins Bcl-2 and Bcl-w. Mutational analyses using SPOT arrays revealed the effects of 170 point mutations made in the background of a peptide derived from the BH3 region of Bim, and a simple predictive model constructed using these data explained much of the specificity observed in our Mcl-1 versus Bcl-x(L) binders.
Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL.,Dutta S, Gulla S, Chen TS, Fire E, Grant RA, Keating AE J Mol Biol. 2010 May 21;398(5):747-62. Epub 2010 Apr 2. PMID:20363230[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
- ↑ Dutta S, Gulla S, Chen TS, Fire E, Grant RA, Keating AE. Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL. J Mol Biol. 2010 May 21;398(5):747-62. Epub 2010 Apr 2. PMID:20363230 doi:10.1016/j.jmb.2010.03.058
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