5uup: Difference between revisions
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==Human Bfl-1 covalently cross-linked to an electrophilic variant of a Bfl-1-specific selected peptide== | |||
<StructureSection load='5uup' size='340' side='right' caption='[[5uup]], [[Resolution|resolution]] 1.73Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5uup]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UUP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UUP 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></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKR:ACRYLIC+ACID'>AKR</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uuk|5uuk]], [[5uul|5uul]], [[5uum|5uum]]</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=5uup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uup OCA], [http://pdbe.org/5uup PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uup RCSB], [http://www.ebi.ac.uk/pdbsum/5uup PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uup ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/B2LA1_HUMAN B2LA1_HUMAN]] Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors. | |||
Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1.,Jenson JM, Ryan JA, Grant RA, Letai A, Keating AE Elife. 2017 Jun 8;6. pii: e25541. doi: 10.7554/eLife.25541. PMID:28594323<ref>PMID:28594323</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5uup" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Grant, R A]] | |||
[[Category: Jenson, J M]] | |||
[[Category: Keating, A E]] | |||
[[Category: Apoptosis]] | |||
[[Category: Apoptosis regulatory protein]] | |||
[[Category: Bcl2 related protein a1]] | |||
[[Category: Bcl2a1]] | |||
[[Category: Electrophile]] | |||
[[Category: Peptide inhibitor]] | |||
[[Category: Protein binding]] | |||
[[Category: Protein structure]] | |||
[[Category: Proto-oncogene]] | |||
[[Category: Specificity]] | |||
Revision as of 10:13, 27 September 2017
Human Bfl-1 covalently cross-linked to an electrophilic variant of a Bfl-1-specific selected peptide
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