6sis
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:ElonginC:ElonginB== | |
| + | <StructureSection load='6sis' size='340' side='right'caption='[[6sis]], [[Resolution|resolution]] 3.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6sis]] 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=6SIS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SIS 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]] 3.5Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LFE:~{N}-[(5~{S},7~{R},11~{S},23~{S})-11-~{tert}-butyl-34-(4-methyl-1,3-thiazol-5-yl)-7-oxidanyl-4,10,13-tris(oxidanylidene)-15,18,21,25,28,31-hexaoxa-3,9,12-triazatricyclo[30.4.0.0^{5,9}]hexatriaconta-1(32),33,35-trien-23-yl]-2-[(7~{S},9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,10,12-tetraen-9-yl]ethanamide'>LFE</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=6sis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sis OCA], [https://pdbe.org/6sis PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6sis RCSB], [https://www.ebi.ac.uk/pdbsum/6sis PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6sis ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets. | ||
| - | + | Structure-Based Design of a Macrocyclic PROTAC.,Ciulli A, Testa A, Hughes SJ, Lucas X, Wright JE Angew Chem Int Ed Engl. 2019 Nov 19. doi: 10.1002/anie.201914396. PMID:31746102<ref>PMID:31746102</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6sis" style="background-color:#fffaf0;"></div> |
| - | [[Category: Ciulli | + | |
| - | [[Category: Hughes | + | ==See Also== |
| + | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
| + | *[[Elongation factor 3D structures|Elongation factor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ciulli A]] | ||
| + | [[Category: Hughes SJ]] | ||
| + | [[Category: Testa A]] | ||
Current revision
Crystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:ElonginC:ElonginB
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