5MVS

Crystal structure of Dot1L in complex with adenosine and inhibitor CPD1 [N6-(2,6-dichlorophenyl)-N6-(pent-2-yn-1-yl)quinoline-4,6-diamine]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Mobitz, H.Machauer, R.Holzer, P.Vaupel, A.Stauffer, F.Ragot, C.Caravatti, G.Scheufler, C.Fernandez, C.Hommel, U.Tiedt, R.Beyer, K.S.Chen, C.Zhu, H.Gaul, C.

(2017) ACS Med Chem Lett 8: 338-343

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00519
  • Primary Citation of Related Structures:  
    5MVS, 5MW3, 5MW4

  • PubMed Abstract: 

    Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2 , a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3 , an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7 , a highly potent, selective and structurally novel Dot1L inhibitor.


  • Organizational Affiliation

    Novartis Institutes for Biomedical Research , 4002 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 
Gene Names: DOT1LKIAA1814KMT4
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
Binding Affinity Annotations 
IDSourceBinding Affinity
ADN Binding MOAD:  5MVS IC50: 1.00e+5 (nM) from 1 assay(s)
BindingDB:  5MVS IC50: 1.00e+5 (nM) from 1 assay(s)
5JJ Binding MOAD:  5MVS IC50: 190 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 158.211α = 90
b = 158.211β = 90
c = 73.826γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-22
    Type: Initial release
  • Version 1.1: 2017-04-05
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description