6HM0
Crystal structure of human BRD9 bromodomain in complex with a PROTAC
Summary for 6HM0
| Entry DOI | 10.2210/pdb6hm0/pdb |
| Descriptor | Bromodomain-containing protein 9, (2~{S},4~{S})-1-[(2~{S})-2-[2-[2-[2-[4-[[2,6-dimethoxy-4-(2-methyl-1-oxidanylidene-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide (3 entities in total) |
| Functional Keywords | protac, lysine-acetylated histone binding, chromatin regulator, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 30405.84 |
| Authors | Hughes, S.J.,Zoppi, V.,Ciulli, A. (deposition date: 2018-09-11, release date: 2019-01-16, Last modification date: 2024-01-24) |
| Primary citation | Zoppi, V.,Hughes, S.J.,Maniaci, C.,Testa, A.,Gmaschitz, T.,Wieshofer, C.,Koegl, M.,Riching, K.M.,Daniels, D.L.,Spallarossa, A.,Ciulli, A. Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel-Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7. J.Med.Chem., 62:699-726, 2019 Cited by PubMed Abstract: Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations. PubMed: 30540463DOI: 10.1021/acs.jmedchem.8b01413 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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