8gcg
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==MDM2 bound to inhibitor== | |
| + | <StructureSection load='8gcg' size='340' side='right'caption='[[8gcg]], [[Resolution|resolution]] 1.47Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8gcg]] is a 2 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=8GCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GCG 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]] 1.47Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1A2I:(2S)-2-(aminomethyl)-3-methylbutanoic+acid'>A1A2I</scene>, <scene name='pdbligand=A1A2J:(2~{S},4~{S})-4-azanyl-1-(phenylcarbonyl)pyrrolidine-2-carboxylic+acid'>A1A2J</scene>, <scene name='pdbligand=A1A2K:(2~{R})-2-azanyl-3-[1-(2-hydroxy-2-oxoethyl)-1,2,3-triazol-4-yl]propanoic+acid'>A1A2K</scene>, <scene name='pdbligand=FX9:(2~{S})-2-azanyl-3-[3-(trifluoromethyl)phenyl]propanoic+acid'>FX9</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=8gcg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gcg OCA], [https://pdbe.org/8gcg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gcg RCSB], [https://www.ebi.ac.uk/pdbsum/8gcg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gcg 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 == | ||
| + | Synthetic macrocyclic peptides are an emerging molecular class for both targeting intracellular protein-protein interactions (PPIs) and providing an oral modality for drug targets typically addressed by biologics. Display technologies, such as mRNA and phage display, often yield peptides that are too large and too polar to achieve passive permeability or oral bioavailability without substantial off-platform medicinal chemistry. Herein, we use DNA-encoded cyclic peptide libraries to discover a neutral nonapeptide, UNP-6457, that inhibits MDM2-p53 interaction with an IC(50) of 8.9 nM. X-ray structural analysis of the MDM2-UNP-6457 complex revealed mutual binding interactions and identified key ligand modification points which may be tuned to enhance its pharmacokinetic profile. These studies showcase how tailored DEL libraries can directly yield macrocyclic peptides benefiting from low MW, TPSA, and HBD/HBA counts that are capable of potently inhibiting therapeutically relevant protein-protein interactions. | ||
| - | + | DNA-Encoded Macrocyclic Peptide Libraries Enable the Discovery of a Neutral MDM2-p53 Inhibitor.,Silvestri AP, Zhang Q, Ping Y, Muir EW, Zhao J, Chakka SK, Wang G, Bray WM, Chen W, Fribourgh JL, Tripathi S, He Y, Rubin SM, Satz AL, Pye CR, Kuai L, Su W, Schwochert JA ACS Med Chem Lett. 2023 May 5;14(6):820-826. doi: 10.1021/acsmedchemlett.3c00117. , eCollection 2023 Jun 8. PMID:37312849<ref>PMID:37312849</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8gcg" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: Muir | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: Silvestri | + | [[Category: Large Structures]] |
| + | [[Category: Synthetic construct]] | ||
| + | [[Category: Chakka SK]] | ||
| + | [[Category: Muir EW]] | ||
| + | [[Category: Pye CR]] | ||
| + | [[Category: Rubin SM]] | ||
| + | [[Category: Schwochert JA]] | ||
| + | [[Category: Silvestri AP]] | ||
| + | [[Category: Tripathi SM]] | ||
Current revision
MDM2 bound to inhibitor
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