5T35

The PROTAC MZ1 in complex with the second bromodomain of Brd4 and pVHL:ElonginC:ElonginB


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural basis of PROTAC cooperative recognition for selective protein degradation.

Gadd, M.S.Testa, A.Lucas, X.Chan, K.H.Chen, W.Lamont, D.J.Zengerle, M.Ciulli, A.

(2017) Nat Chem Biol 13: 514-521

  • DOI: https://doi.org/10.1038/nchembio.2329
  • Primary Citation of Related Structures:  
    5T35

  • PubMed Abstract: 

    Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4 BD2 ). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4 BD2 . Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.


  • Organizational Affiliation

    Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4
A, E
130Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
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Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Transcription elongation factor B polypeptide 2
B, F
104Homo sapiensMutation(s): 0 
Gene Names: TCEB2
UniProt & NIH Common Fund Data Resources
Find proteins for Q15370 (Homo sapiens)
Explore Q15370 
Go to UniProtKB:  Q15370
PHAROS:  Q15370
GTEx:  ENSG00000103363 
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UniProt GroupQ15370
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Transcription elongation factor B polypeptide 1
C, G
97Homo sapiensMutation(s): 0 
Gene Names: TCEB1
UniProt & NIH Common Fund Data Resources
Find proteins for Q15369 (Homo sapiens)
Explore Q15369 
Go to UniProtKB:  Q15369
PHAROS:  Q15369
GTEx:  ENSG00000154582 
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UniProt GroupQ15369
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Von Hippel-Lindau disease tumor suppressor
D, H
162Homo sapiensMutation(s): 0 
Gene Names: VHL
UniProt & NIH Common Fund Data Resources
Find proteins for P40337 (Homo sapiens)
Explore P40337 
Go to UniProtKB:  P40337
PHAROS:  P40337
GTEx:  ENSG00000134086 
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UniProt GroupP40337
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
759
Query on 759

Download Ideal Coordinates CCD File 
I [auth D],
J [auth H]
(2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[(9~{S})-7-(4-chlorophenyl)-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]ethanoylamino]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-2,3-dihydro-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
C49 H62 Cl N9 O8 S2
HJITZUXCPZGZPX-PYNGZGNASA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.207 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.306α = 90
b = 102.306β = 90
c = 144.329γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research CouncilERC-2012-StG-311460

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-08
    Type: Initial release
  • Version 1.1: 2017-03-22
    Changes: Database references
  • Version 1.2: 2017-04-26
    Changes: Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description