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==Crystal structure of hDM2 in complex with a C-terminal triurea capped peptide chimera foldamer.== | ==Crystal structure of hDM2 in complex with a C-terminal triurea capped peptide chimera foldamer.== | ||
<StructureSection load='6hfa' size='340' side='right'caption='[[6hfa]]' scene=''> | <StructureSection load='6hfa' size='340' side='right'caption='[[6hfa]], [[Resolution|resolution]] 1.79Å' 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=6HFA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6HFA FirstGlance]. <br> | <table><tr><td colspan='2'>[[6hfa]] 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=6HFA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6HFA FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6hfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hfa OCA], [http://pdbe.org/6hfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hfa RCSB], [http://www.ebi.ac.uk/pdbsum/6hfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hfa ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UCV:1-[(2~{S})-2-azanyl-3-methyl-butyl]urea'>UCV</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=G2B:'>G2B</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MDM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6hfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hfa OCA], [http://pdbe.org/6hfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hfa RCSB], [http://www.ebi.ac.uk/pdbsum/6hfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hfa ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/MDM2_HUMAN MDM2_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.<ref>PMID:12821780</ref> <ref>PMID:15053880</ref> <ref>PMID:15195100</ref> <ref>PMID:16337594</ref> <ref>PMID:15632057</ref> <ref>PMID:17290220</ref> <ref>PMID:19098711</ref> <ref>PMID:19219073</ref> <ref>PMID:19965871</ref> <ref>PMID:20858735</ref> <ref>PMID:20173098</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization. | |||
Structural Basis for alpha-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.,Cussol L, Mauran-Ambrosino L, Buratto J, Belorusova AY, Neuville M, Osz J, Fribourg S, Fremaux J, Dolain C, Goudreau SR, Rochel N, Guichard G Angew Chem Int Ed Engl. 2020 Sep 16. doi: 10.1002/anie.202008992. PMID:32935897<ref>PMID:32935897</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6hfa" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Buratto J]] | [[Category: RING-type E3 ubiquitin transferase]] | ||
[[Category: Fribourg S]] | [[Category: Buratto, J]] | ||
[[Category: Goudreau S]] | [[Category: Fribourg, S]] | ||
[[Category: Guichard G]] | [[Category: Goudreau, S]] | ||
[[Category: Mauran L]] | [[Category: Guichard, G]] | ||
[[Category: Mauran, L]] | |||
[[Category: Oncoprotein]] | |||
[[Category: Protein foldamer complex]] | |||
[[Category: Protein protein interaction inhibitor]] | |||
[[Category: Urea based chimera foldamer]] | |||
Revision as of 11:16, 20 January 2021
Crystal structure of hDM2 in complex with a C-terminal triurea capped peptide chimera foldamer.Crystal structure of hDM2 in complex with a C-terminal triurea capped peptide chimera foldamer.
Structural highlights
Disease[MDM2_HUMAN] Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. Function[MDM2_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedEfficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization. Structural Basis for alpha-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.,Cussol L, Mauran-Ambrosino L, Buratto J, Belorusova AY, Neuville M, Osz J, Fribourg S, Fremaux J, Dolain C, Goudreau SR, Rochel N, Guichard G Angew Chem Int Ed Engl. 2020 Sep 16. doi: 10.1002/anie.202008992. PMID:32935897[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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