8TE4

Crystal structure of the methyltransferase domain of R882H/N879A DNMT3A homotetramer


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.203 

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Ligand Structure Quality Assessment 


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Literature

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.

Lu, J.Guo, Y.Yin, J.Chen, J.Wang, Y.Wang, G.G.Song, J.

(2024) Nat Commun 15: 3111-3111

  • DOI: https://doi.org/10.1038/s41467-024-47398-y
  • Primary Citation of Related Structures:  
    8TDR, 8TE1, 8TE3, 8TE4

  • PubMed Abstract: 

    DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.


  • Organizational Affiliation

    Department of Biochemistry, University of California, Riverside, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA (cytosine-5)-methyltransferase 3A287Homo sapiensMutation(s): 2 
Gene Names: DNMT3A
EC: 2.1.1.37 (PDB Primary Data), 2.1.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6K1 (Homo sapiens)
Explore Q9Y6K1 
Go to UniProtKB:  Q9Y6K1
PHAROS:  Q9Y6K1
GTEx:  ENSG00000119772 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6K1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SAH (Subject of Investigation/LOI)
Query on SAH

Download Ideal Coordinates CCD File 
I [auth A],
O [auth B],
U [auth C],
X [auth D]
S-ADENOSYL-L-HOMOCYSTEINE
C14 H20 N6 O5 S
ZJUKTBDSGOFHSH-WFMPWKQPSA-N
GOL (Subject of Investigation/LOI)
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth D]
BA [auth D]
J [auth A]
K [auth A]
L [auth A]
AA [auth D],
BA [auth D],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
V [auth C],
W [auth C],
Y [auth D],
Z [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SAH BindingDB:  8TE4 IC50: 5.00e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.203 
  • Space Group: P 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 178.068α = 90
b = 178.068β = 90
c = 109.909γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2024-03-13
    Type: Initial release
  • Version 1.1: 2024-09-25
    Changes: Data collection, Database references