8g46
From Proteopedia
(Difference between revisions)
| Line 4: | Line 4: | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8g46]] is a 4 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=8G46 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G46 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8g46]] is a 4 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=8G46 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G46 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YK3:tert-butyl+[( | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YK3:~{tert}-butyl+2-[(9~{S})-7-[4-(ethylsulfonylamino)phenyl]-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoate'>YK3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8g46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g46 OCA], [https://pdbe.org/8g46 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g46 RCSB], [https://www.ebi.ac.uk/pdbsum/8g46 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g46 ProSAT]</span></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=8g46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g46 OCA], [https://pdbe.org/8g46 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g46 RCSB], [https://www.ebi.ac.uk/pdbsum/8g46 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g46 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| Line 11: | Line 12: | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| - | Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics (1-3) . Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs (4-6) . The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans -labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4 (DCAF16) ligase to the second bromodomain of BRD4 (BRD4 (BD2) ). BRD4 (BD2) , in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 A cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4 (BD2) have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16 (Cys58) covalent modification. Systematic mutagenesis of both DCAF16 and BRD4 (BD2) revealed that the loop conformation around BRD4 (His437) , rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology. | + | Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics(1-3). Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs(4-6). The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4(DCAF16) ligase to the second bromodomain of BRD4 (BRD4(BD2)). BRD4(BD2), in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 A cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4(BD2) have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16(Cys58) covalent modification. Systematic mutagenesis of both DCAF16 and BRD4(BD2) revealed that the loop conformation around BRD4(His437), rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology. |
| - | Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.,Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Lumpkin R, Sandoval B, Jin CY, Ficarro SB, Wang MY, Xu S, Groendyke BJ, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Marto JA, Qi J, Nowak RP, Donovan KA, Slabicki M, Gray NS, Fischer ES, Ebert BL bioRxiv. 2023 Feb 15:2023.02.14.528208. doi: 10.1101/2023.02.14.528208 | + | Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.,Li YD, Ma MW, Hassan MM, Hunkeler M, Teng M, Puvar K, Lumpkin R, Sandoval B, Jin CY, Ficarro SB, Wang MY, Xu S, Groendyke BJ, Sigua LH, Tavares I, Zou C, Tsai JM, Park PMC, Yoon H, Majewski FC, Marto JA, Qi J, Nowak RP, Donovan KA, Slabicki M, Gray NS, Fischer ES, Ebert BL bioRxiv [Preprint]. 2023 Feb 15:2023.02.14.528208. doi: , 10.1101/2023.02.14.528208. PMID:36824856<ref>PMID:36824856</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Cryo-EM structure of DDB1deltaB-DDA1-DCAF16-BRD4(BD2)-MMH2
| |||||||||||
