4bpi: Difference between revisions
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==Mcl-1 bound to alpha beta Puma BH3 peptide 2== | |||
<StructureSection load='4bpi' size='340' side='right' caption='[[4bpi]], [[Resolution|resolution]] 1.98Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bpi]] is a 2 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=4BPI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BPI FirstGlance]. <br> | |||
==Function== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3A:(3S)-3-AMINOBUTANOIC+ACID'>B3A</scene>, <scene name='pdbligand=B3D:3-AMINOPENTANEDIOIC+ACID'>B3D</scene>, <scene name='pdbligand=B3E:(3S)-3-AMINOHEXANEDIOIC+ACID'>B3E</scene>, <scene name='pdbligand=B3Q:(3S)-3,6-DIAMINO-6-OXOHEXANOIC+ACID'>B3Q</scene>, <scene name='pdbligand=HR7:(3S)-3-AMINO-6-[(DIAMINOMETHYLIDENE)AMINO]HEXANOIC+ACID'>HR7</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bpj|4bpj]], [[4bpk|4bpk]]</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=4bpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bpi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bpi RCSB], [http://www.ebi.ac.uk/pdbsum/4bpi PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE]] 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. | [[http://www.uniprot.org/uniprot/MCL1_MOUSE MCL1_MOUSE]] 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. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported alpha/beta-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived alpha/beta-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three alpha residues of the original alpha/beta backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new alpha/beta-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners. | |||
Structure-guided rational design of alpha/beta-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.,Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD Chembiochem. 2013 Sep 2;14(13):1564-72. doi: 10.1002/cbic.201300351. Epub 2013, Aug 8. PMID:23929624<ref>PMID:23929624</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
[[Category: Checco, J W | == References == | ||
[[Category: Fairlie, W D | <references/> | ||
[[Category: Gellman, S H | __TOC__ | ||
[[Category: Lee, E F | </StructureSection> | ||
[[Category: Smith, B J | [[Category: Human]] | ||
[[Category: Checco, J W]] | |||
[[Category: Fairlie, W D]] | |||
[[Category: Gellman, S H]] | |||
[[Category: Lee, E F]] | |||
[[Category: Smith, B J]] | |||
[[Category: Apoptosis]] | [[Category: Apoptosis]] | ||
[[Category: Bim]] | [[Category: Bim]] | ||
[[Category: Chimera]] | [[Category: Chimera]] | ||
