8g1p

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Current revision (12:38, 26 July 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 8g1p is ON HOLD until Paper Publication
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==Co-crystal structure of Compound 11 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB==
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<StructureSection load='8g1p' size='340' side='right'caption='[[8g1p]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8g1p]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G1P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G1P FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FWZ:(2~{S},4~{R})-~{N}-[[2-[2-[4-[[4-[3-azanyl-6-(2-hydroxyphenyl)pyridazin-4-yl]piperazin-1-yl]methyl]phenyl]ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide'>FWZ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8g1p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g1p OCA], [https://pdbe.org/8g1p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g1p RCSB], [https://www.ebi.ac.uk/pdbsum/8g1p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g1p ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ELOB_HUMAN ELOB_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).<ref>PMID:7638163</ref> <ref>PMID:15590694</ref> The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.<ref>PMID:7638163</ref> <ref>PMID:15590694</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Targeted protein degradation via "hijacking" of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel-Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC's architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.
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Authors: Ghimire Rijal, S., Wurz, R.P., Vaish, A.
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Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.,Wurz RP, Rui H, Dellamaggiore K, Ghimire-Rijal S, Choi K, Smither K, Amegadzie A, Chen N, Li X, Banerjee A, Chen Q, Mohl D, Vaish A Nat Commun. 2023 Jul 13;14(1):4177. doi: 10.1038/s41467-023-39904-5. PMID:37443112<ref>PMID:37443112</ref>
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Description: Co-crystal structure of Compound 11 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Wurz, R.P]]
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<div class="pdbe-citations 8g1p" style="background-color:#fffaf0;"></div>
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[[Category: Vaish, A]]
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== References ==
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[[Category: Ghimire Rijal, S]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Ghimire Rijal S]]
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[[Category: Vaish A]]
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[[Category: Wurz RP]]

Current revision

Co-crystal structure of Compound 11 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB

PDB ID 8g1p

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