View source for 9gfk


==human MDM2 complex with stapled foldamer==
<StructureSection load='9gfk' size='340' side='right'caption='[[9gfk]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9gfk]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9GFK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9GFK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.841&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IL6:(2~{S},4~{S})-4-hexylsulfanylpyrrolidine-2-carboxylic+acid'>A1IL6</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=URL:[(2~{S})-2-azanyl-4-methyl-pentyl]carbamic+acid'>URL</scene></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=9gfk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9gfk OCA], [https://pdbe.org/9gfk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9gfk RCSB], [https://www.ebi.ac.uk/pdbsum/9gfk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9gfk ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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 ==
[https://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 ==
Structural analysis of a co-crystal of a helically-folded peptide-foldamer hybrid in complex with hDM2 E3 ubiquitin ligase, revealed a unique orientation for the C-terminal proline with the pyrrolidine ring pointing backwards in the sequence, and suggested new opportunities for macrocyclization. In particular, we found that the C-terminal prolyl residue could be replaced by its (2S,4S)-4-mercaptoprolyl analogue for optimal bisthioether crosslinking with a cysteine residue installed at position 4 in the sequence. The resulting i,i+7 stapled peptide-foldamer is a high-affinity binder to hDM2, is cell permeable and restores the p53 signalling pathway in p53wt cancer cells. The co-crystal structure of hDM2 and the stapled peptide-foldamer hybrid was determined at 1.84 A, fully validating the original design and further highlighting the potential of cis-4-mercaptoproline in the context of peptide and foldamer stapling.

Optimal Stapling of a Helical Peptide-Foldamer Hybrid Using a C-Terminal 4-Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity.,Neuville M, Bourgeais M, Buratto J, Saragaglia C, Li B, Galeano-Otero I, Mauran L, Varajao L, Goudreau SR, Kauffmann B, Thinon E, Pasco M, Khatib AM, Guichard G Chemistry. 2025 Feb 27:e202403330. doi: 10.1002/chem.202403330. PMID:40014761<ref>PMID:40014761</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9gfk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Bo L]]
[[Category: Bourgeais M]]
[[Category: Buratto J]]
[[Category: Goudreau SR]]
[[Category: Kauffmann B]]
[[Category: Khatib AM]]
[[Category: Mauran L]]
[[Category: Neuville M]]
[[Category: Pasco M]]
[[Category: Saragaglia C]]
[[Category: Thinon E]]
[[Category: Varajao L]]