5uum: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 5uum is ~~ON HOLD~~ ~~until Paper~~ Publication

==Human Mcl-1 in complex with a Bfl-1-specific selected peptide==

== Structural highlights ==

<table><tr><td colspan='2'>[[5uum]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UUM 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>

<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=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]], [[5uup|5uup]]</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=5uum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uum OCA], [http://pdbe.org/5uum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uum RCSB], [http://www.ebi.ac.uk/pdbsum/5uum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uum ProSAT]</span></td></tr>

</table>

== 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>

== 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.

~~Authors~~:

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>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased Structures~~]]

</div>

== 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: Peptide inhibitor]]

[[Category: Peptide library]]

[[Category: Protein binding]]

[[Category: Protein structure]]

[[Category: Proto-oncogene]]

[[Category: Specificity]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5uum is ON HOLD  until Paper Publication
+==Human Mcl-1 in complex with a Bfl-1-specific selected peptide==
+<StructureSection load='5uum' size='340' side='right' caption='[[5uum]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5uum]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UUM 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>
+<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=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]], [[5uup|5uup]]</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=5uum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uum OCA], [http://pdbe.org/5uum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uum RCSB], [http://www.ebi.ac.uk/pdbsum/5uum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uum ProSAT]</span></td></tr>
+</table>
+== 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>
+<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 &gt; 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.
-Authors:
+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>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5uum" 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: Peptide inhibitor]]
+[[Category: Peptide library]]
+[[Category: Protein binding]]
+[[Category: Protein structure]]
+[[Category: Proto-oncogene]]
+[[Category: Specificity]]