6TEL

Crystal structure of Dot1L in complex with an inhibitor (compound 10).

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

New Potent DOT1L Inhibitors forin VivoEvaluation in Mouse.

Stauffer, F., Weiss, A., Scheufler, C., Mobitz, H., Ragot, C., Beyer, K.S., Calkins, K., Guthy, D., Kiffe, M., Van Eerdenbrugh, B., Tiedt, R., Gaul, C.

(2019) ACS Med Chem Lett 10: 1655-1660

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00452
  • Primary Citation of Related Structures:  
    6TE6, 6TEL, 6TEN

  • PubMed Abstract: 

    In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

    • Organizational Affiliation: 

    Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histone-lysine N-methyltransferase, H3 lysine-79 specific
A, B
334Homo sapiensMutation(s): 0 
EC: 2.1.1.43
UniProt & NIH Common Fund Data Resources
Find proteins for Q8TEK3 (Homo sapiens)
Explore Q8TEK3 
Go to UniProtKB:  Q8TEK3
PHAROS:  Q8TEK3
GTEx:  ENSG00000104885 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8TEK3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
N4Z (Subject of Investigation/LOI)
Query on N4Z
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		~{N}1-[(~{S})-[2,2-bis(fluoranyl)-1,3-benzodioxol-4-yl]-(3-chloranylpyridin-2-yl)methyl]-~{N}2-(4-methoxy-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-methylsulfonyl-benzene-1,2-diamine
C28 H27 Cl F2 N8 O5 S
QJIMSJUUARCROQ-QFIPXVFZSA-N
K
Query on K
Download Ideal Coordinates CCD File 
E [auth B]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
N4Z Binding MOAD:  6TEL IC50: 0.11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 159.16α = 90
b = 159.16β = 90
c = 74.14γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


View more in-depth experimental data
Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-11
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description