6w8j

From Proteopedia

Structure of DNMT3A (R882H) in complex with CAG DNA

PDB ID 6w8j

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Structural highlights

6w8j is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.445Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DNM3A_HUMAN Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZNF238. Can actively repress transcription through the recruitment of HDAC activity (By similarity).^[1]

Publication Abstract from PubMed

DNA methyltransferase DNMT3A is essential for establishment of mammalian DNA methylation during development. The R882H DNMT3A is a hotspot mutation in acute myeloid leukemia (AML) causing aberrant DNA methylation. However, how this mutation affects the structure and function of DNMT3A remains unclear. Here we report structural characterization of wild-type and R882H-mutated DNMT3A in complex with DNA substrates with different sequence contexts. A loop from the target recognition domain (TRD loop) recognizes the CpG dinucleotides in a +1 flanking site-dependent manner. The R882H mutation reduces the DNA binding at the homodimeric interface, as well as the molecular link between the homodimeric interface and TRD loop, leading to enhanced dynamics of TRD loop. Consistently, in vitro methylation analyses indicate that the R882H mutation compromises the enzymatic activity, CpG specificity and flanking sequence preference of DNMT3A. Together, this study uncovers multiple defects of DNMT3A caused by the R882H mutation in AML.

Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation.,Anteneh H, Fang J, Song J Nat Commun. 2020 May 8;11(1):2294. doi: 10.1038/s41467-020-16213-9. PMID:32385248^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
↑ Anteneh H, Fang J, Song J. Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation. Nat Commun. 2020 May 8;11(1):2294. doi: 10.1038/s41467-020-16213-9. PMID:32385248 doi:http://dx.doi.org/10.1038/s41467-020-16213-9