6T1J

Crystal structure of MLLT1 (ENL) YEATS domain in complexed with piperazine-urea derivative 2

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history. 


Literature

Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1.

Ni, X., Heidenreich, D., Christott, T., Bennett, J., Moustakim, M., Brennan, P.E., Fedorov, O., Knapp, S., Chaikuad, A.

(2019) ACS Med Chem Lett 10: 1661-1666

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00460
  • Primary Citation of Related Structures:  
    6T1I, 6T1J, 6T1L, 6T1M, 6T1N, 6T1O

  • PubMed Abstract: 

    YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.

    • Organizational Affiliation: 

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein ENL154Homo sapiensMutation(s): 0 
Gene Names: MLLT1, ENL, LTG19, YEATS1
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
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
M7T (Subject of Investigation/LOI)
Query on M7T
Download Ideal Coordinates CCD File 
I [auth A]~{N}-[[4-(pyrrolidin-1-ylmethyl)phenyl]methyl]-4-thiophen-2-ylcarbonyl-piperazine-1-carboxamide
C22 H28 N4 O2 S
UTOUOHONUGPBCF-UHFFFAOYSA-N
EDO
Query on EDO
Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
M7T BindingDB:  6T1J Kd: 1.81e+4 (nM) from 1 assay(s)
IC50: 1.07e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.152α = 90
b = 49.152β = 90
c = 131.009γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-11-06
    Type: Initial release
  • Version 1.1: 2020-01-29
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description