6hm0

From Proteopedia

Crystal structure of human BRD9 bromodomain in complex with a PROTAC

PDB ID 6hm0

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Structural highlights

6hm0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BRD9_HUMAN May play a role in chromatin remodeling and regulation of transcription.

Publication Abstract from PubMed

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.

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.,Zoppi V, Hughes SJ, Maniaci C, Testa A, Gmaschitz T, Wieshofer C, Koegl M, Riching K, Daniels DL, Spallarossa A, Ciulli A J Med Chem. 2018 Dec 12. doi: 10.1021/acs.jmedchem.8b01413. PMID:30540463^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zoppi V, Hughes SJ, Maniaci C, Testa A, Gmaschitz T, Wieshofer C, Koegl M, Riching K, Daniels DL, 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. 2018 Dec 12. doi: 10.1021/acs.jmedchem.8b01413. PMID:30540463 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01413