5DRY

Crystal structure of Dot1L in complex with inhibitor CPD3 [N-(1-(2-chlorophenyl)-1H-indol-6-yl)-2-(2-(5-(2-chlorophenyl)-1H-tetrazol-1-yl)acetyl)hydrazinecarboxamide]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.

Chen, C.Zhu, H.Stauffer, F.Caravatti, G.Vollmer, S.Machauer, R.Holzer, P.Mobitz, H.Scheufler, C.Klumpp, M.Tiedt, R.Beyer, K.S.Calkins, K.Guthy, D.Kiffe, M.Zhang, J.Gaul, C.

(2016) ACS Med Chem Lett 7: 735-740

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00167
  • Primary Citation of Related Structures:  
    5DRT, 5DRY, 5DSX, 5DT2

  • PubMed Abstract: 

    Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.


  • Organizational Affiliation

    Novartis Institutes for Biomedical Research , Shanghai 201203, China.


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
5EK Binding MOAD:  5DRY IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 158.76α = 90
b = 158.76β = 90
c = 74.46γ = 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: 2016-06-15
    Type: Initial release
  • Version 1.1: 2016-09-07
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description