6v4e: Difference between revisions
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==Crystal Structure Analysis of Zebra Fish MDM== | ==Crystal Structure Analysis of Zebra Fish MDM== | ||
<StructureSection load='6v4e' size='340' side='right'caption='[[6v4e]]' scene=''> | <StructureSection load='6v4e' size='340' side='right'caption='[[6v4e]], [[Resolution|resolution]] 1.62Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V4E OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6v4e]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V4E FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0EH:(2R)-2-AMINO-2-METHYLNONANOIC+ACID'>0EH</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mdm4, mdmx ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Brachidanio rerio])</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=6v4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v4e OCA], [https://pdbe.org/6v4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v4e RCSB], [https://www.ebi.ac.uk/pdbsum/6v4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v4e ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/MDM4_DANRE MDM4_DANRE]] Inhibits p53- and p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
p53 is a critical tumor-suppressor protein that guards the human genome against mutations by inducing cell-cycle arrest or apoptosis. Cancer cells subvert p53 by deletion, mutation, or overexpression of the negative regulators HDM2 and HDMX. For tumors that retain wild-type p53, its reactivation by pharmacologic targeting of HDM2 and/or HDMX represents a promising strategy, with a series of selective small-molecule HDM2 inhibitors and a dual HDM2/HDMX stapled-peptide inhibitor being evaluated in clinical trials. Because selective HDM2 targeting can cause hematologic toxicity, selective HDMX inhibitors could provide an alternative p53-reactivation strategy, but clinical candidates remain elusive. Here, we applied a mutation-scanning approach to uncover p53-based stapled peptides that are selective for HDMX. Crystal structures of stapled-peptide/HDMX complexes revealed a molecular mechanism for the observed specificity, which was validated by HDMX mutagenesis. Thus, we provide a blueprint for the development of HDMX-selective inhibitors to dissect and target the p53/HDMX interaction. | |||
Identification of a Structural Determinant for Selective Targeting of HDMX.,Ben-Nun Y, Seo HS, Harvey EP, Hauseman ZJ, Wales TE, Newman CE, Cathcart AM, Engen JR, Dhe-Paganon S, Walensky LD Structure. 2020 Jul 7;28(7):847-857.e5. doi: 10.1016/j.str.2020.04.011. Epub 2020, Apr 30. PMID:32359398<ref>PMID:32359398</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6v4e" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[MDM4|MDM4]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Brachidanio rerio]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Dhe-Paganon S]] | [[Category: Dhe-Paganon, S]] | ||
[[Category: Seo H | [[Category: Seo, H S]] | ||
[[Category: Apoptosis]] | |||
[[Category: P53 binding]] | |||
Revision as of 11:58, 5 May 2021
Crystal Structure Analysis of Zebra Fish MDMCrystal Structure Analysis of Zebra Fish MDM
Structural highlights
Function[MDM4_DANRE] Inhibits p53- and p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain (By similarity). Publication Abstract from PubMedp53 is a critical tumor-suppressor protein that guards the human genome against mutations by inducing cell-cycle arrest or apoptosis. Cancer cells subvert p53 by deletion, mutation, or overexpression of the negative regulators HDM2 and HDMX. For tumors that retain wild-type p53, its reactivation by pharmacologic targeting of HDM2 and/or HDMX represents a promising strategy, with a series of selective small-molecule HDM2 inhibitors and a dual HDM2/HDMX stapled-peptide inhibitor being evaluated in clinical trials. Because selective HDM2 targeting can cause hematologic toxicity, selective HDMX inhibitors could provide an alternative p53-reactivation strategy, but clinical candidates remain elusive. Here, we applied a mutation-scanning approach to uncover p53-based stapled peptides that are selective for HDMX. Crystal structures of stapled-peptide/HDMX complexes revealed a molecular mechanism for the observed specificity, which was validated by HDMX mutagenesis. Thus, we provide a blueprint for the development of HDMX-selective inhibitors to dissect and target the p53/HDMX interaction. Identification of a Structural Determinant for Selective Targeting of HDMX.,Ben-Nun Y, Seo HS, Harvey EP, Hauseman ZJ, Wales TE, Newman CE, Cathcart AM, Engen JR, Dhe-Paganon S, Walensky LD Structure. 2020 Jul 7;28(7):847-857.e5. doi: 10.1016/j.str.2020.04.011. Epub 2020, Apr 30. PMID:32359398[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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