6BOY

Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET6 PROTAC.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.33 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Plasticity in binding confers selectivity in ligand-induced protein degradation.

Nowak, R.P.DeAngelo, S.L.Buckley, D.He, Z.Donovan, K.A.An, J.Safaee, N.Jedrychowski, M.P.Ponthier, C.M.Ishoey, M.Zhang, T.Mancias, J.D.Gray, N.S.Bradner, J.E.Fischer, E.S.

(2018) Nat Chem Biol 14: 706-714

  • DOI: https://doi.org/10.1038/s41589-018-0055-y
  • Primary Citation of Related Structures:  
    6BN7, 6BN8, 6BN9, 6BNB, 6BOY

  • PubMed Abstract: 

    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 a 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 that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.


  • Organizational Affiliation

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA damage-binding protein 1864Homo sapiensMutation(s): 0 
Gene Names: DDB1XAP1
UniProt & NIH Common Fund Data Resources
Find proteins for Q16531 (Homo sapiens)
Explore Q16531 
Go to UniProtKB:  Q16531
PHAROS:  Q16531
GTEx:  ENSG00000167986 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16531
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Protein cereblon463Homo sapiensMutation(s): 0 
Gene Names: CRBNAD-006
UniProt & NIH Common Fund Data Resources
Find proteins for Q96SW2 (Homo sapiens)
Explore Q96SW2 
Go to UniProtKB:  Q96SW2
PHAROS:  Q96SW2
GTEx:  ENSG00000113851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96SW2
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo sapiensMutation(s): 1 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RN6 (Subject of Investigation/LOI)
Query on RN6

Download Ideal Coordinates CCD File 
E [auth B]2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-(8-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}octyl)acetamide
C42 H45 Cl N8 O7 S
JGQPZPLJOBHHBK-KYJUHHDHSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth B]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.33 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 115.406α = 90
b = 115.406β = 90
c = 588.143γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesNCI R01CA214608
The Harvard University William F. Milton FundUnited States--
the Friends of Dana FarberUnited States--
the Claudia Adams Barr Program for Innovative Cancer ResearchUnited States--
the Linde Family FoundationUnited States--

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-30
    Type: Initial release
  • Version 1.1: 2018-08-01
    Changes: Data collection, Database references
  • Version 1.2: 2018-11-07
    Changes: Data collection, Database references
  • Version 1.3: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.4: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.5: 2023-10-04
    Changes: Data collection, Database references, Refinement description