6HT1

Crystal structure of MLLT1 (ENL) YEATS domain in complexed with SGC-iMLLT (compound 92)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Moustakim, M.Christott, T.Monteiro, O.P.Bennett, J.Giroud, C.Ward, J.Rogers, C.M.Smith, P.Panagakou, I.Diaz-Saez, L.Felce, S.L.Gamble, V.Gileadi, C.Halidi, N.Heidenreich, D.Chaikuad, A.Knapp, S.Huber, K.V.M.Farnie, G.Heer, J.Manevski, N.Poda, G.Al-Awar, R.Dixon, D.J.Brennan, P.E.Fedorov, O.

(2018) Angew Chem Int Ed Engl 57: 16302-16307

  • DOI: https://doi.org/10.1002/anie.201810617
  • Primary Citation of Related Structures:  
    6HT0, 6HT1

  • PubMed Abstract: 

    YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.


  • Organizational Affiliation

    Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein ENL155Homo sapiensMutation(s): 0 
Gene Names: MLLT1ENLLTG19YEATS1
UniProt & NIH Common Fund Data Resources
Find proteins for Q03111 (Homo sapiens)
Explore Q03111 
Go to UniProtKB:  Q03111
PHAROS:  Q03111
GTEx:  ENSG00000130382 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ03111
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GQ5
Query on GQ5

Download Ideal Coordinates CCD File 
K [auth A]1-methyl-~{N}-[2-[[(2~{S})-2-methylpyrrolidin-1-yl]methyl]-3~{H}-benzimidazol-5-yl]indazole-5-carboxamide
C22 H24 N6 O
QGNDVASWIHEXCL-AWEZNQCLSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.203 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.842α = 90
b = 48.842β = 90
c = 133.238γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2018-10-17
    Type: Initial release
  • Version 1.1: 2018-12-12
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description