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PXD008689

DataSet Summary

  • HostingRepository: PRIDE
  • AnnounceDate: 2018-05-16
  • AnnouncementXML: Submission_2018-05-16_06:52:02.xml
  • DigitalObjectIdentifier:
  • ReviewLevel: Peer-reviewed dataset
  • DatasetOrigin: Original data
  • RepositorySupport: Unsupported dataset by repository
  • PrimarySubmitter: Eric Fischer
  • Title: Plasticity of inter-protein contacts confers selectivity in ligand induced protein degradation dataset 1
  • Description: Heterobifunctional small molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize comprehensive characterization of the ligand dependent CRBN/BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low energy binding conformations, which are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying inter-protein contacts and inform the design of the first BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic inter-protein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.
  • SpeciesList: scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
  • ModificationList: No PTMs are included in the dataset
  • Instrument: Orbitrap Fusion Lumos

Dataset History

VersionDatetimeStatusChangeLog Entry
02018-01-16 05:24:39ID requested
12018-05-16 06:52:03announced

Publication List

  1. Dataset with its publication pending

Keyword List

  1. curator keyword: Biological
  2. submitter keyword: PROTAC, ubiquitin, ligase, degrader, crbn

Contact List

    Eric Sebastian Fischer
    • contact affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
    • contact email: eric_fischer@dfci.harvard.edu
    • lab head:
    Eric Fischer
    • contact affiliation: Dana-Farber Cancer Institute
    • contact email: eric_fischer@dfci.harvard.edu
    • dataset submitter:

Full Dataset Link List

  1. Dataset FTP location
  2. PRIDE project URI
Repository Record List
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