Molecule Information

General Information of the Molecule (ID: Mol00328)
Name
DNA (cytosine-5)-methyltransferase 3A (DNMT3A) ,Homo sapiens
Synonyms
Dnmt3a; Cysteine methyltransferase DNMT3A; DNA methyltransferase HsaIIIA; DNA MTase HsaIIIA; M.HsaIIIA
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Molecule Type
Protein
Gene Name
DNMT3A
Gene ID
1788
Location
chr2:25227855-25342590[-]
Sequence
MPAMPSSGPGDTSSSAAEREEDRKDGEEQEEPRGKEERQEPSTTARKVGRPGRKRKHPPV
ESGDTPKDPAVISKSPSMAQDSGASELLPNGDLEKRSEPQPEEGSPAGGQKGGAPAEGEG
AAETLPEASRAVENGCCTPKEGRGAPAEAGKEQKETNIESMKMEGSRGRLRGGLGWESSL
RQRPMPRLTFQAGDPYYISKRKRDEWLARWKREAEKKAKVIAGMNAVEENQGPGESQKVE
EASPPAVQQPTDPASPTVATTPEPVGSDAGDKNATKAGDDEPEYEDGRGFGIGELVWGKL
RGFSWWPGRIVSWWMTGRSRAAEGTRWVMWFGDGKFSVVCVEKLMPLSSFCSAFHQATYN
KQPMYRKAIYEVLQVASSRAGKLFPVCHDSDESDTAKAVEVQNKPMIEWALGGFQPSGPK
GLEPPEEEKNPYKEVYTDMWVEPEAAAYAPPPPAKKPRKSTAEKPKVKEIIDERTRERLV
YEVRQKCRNIEDICISCGSLNVTLEHPLFVGGMCQNCKNCFLECAYQYDDDGYQSYCTIC
CGGREVLMCGNNNCCRCFCVECVDLLVGPGAAQAAIKEDPWNCYMCGHKGTYGLLRRRED
WPSRLQMFFANNHDQEFDPPKVYPPVPAEKRKPIRVLSLFDGIATGLLVLKDLGIQVDRY
IASEVCEDSITVGMVRHQGKIMYVGDVRSVTQKHIQEWGPFDLVIGGSPCNDLSIVNPAR
KGLYEGTGRLFFEFYRLLHDARPKEGDDRPFFWLFENVVAMGVSDKRDISRFLESNPVMI
DAKEVSAAHRARYFWGNLPGMNRPLASTVNDKLELQECLEHGRIAKFSKVRTITTRSNSI
KQGKDQHFPVFMNEKEDILWCTEMERVFGFPVHYTDVSNMSRLARQRLLGRSWSVPVIRH
LFAPLKEYFACV
    Click to Show/Hide
3D-structure
PDB ID
4U7P
Classification
Transferase/transferase regulator
Method
X-ray diffraction
Resolution
3.82  Å
Function
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 ZBTB18. Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. Can actively repress transcription through the recruitment of HDAC activity. Also has weak auto-methylation activity on Cys-710 in absence of DNA.
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Uniprot ID
DNM3A_HUMAN
Ensembl ID
ENSG00000119772
HGNC ID
HGNC:2978
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule with Structure Alteration
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Daunorubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [1]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug Daunorubicin
 Drug Info 
Molecule Alteration Missense mutation
p.R882H
Wild Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 6W8B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.44  Å
PDB: 6W8J
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.46
TM score: 0.99493
Amino acid change:
R882H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
A
A
E
E
630
|
K
K
R
R
K
K
P
P
I
I
R
R
V
V
L
L
S
S
L
L
640
|
F
F
D
D
G
G
I
I
A
A
T
T
G
G
L
L
L
L
V
V
650
|
L
L
K
K
D
D
L
L
G
G
I
I
Q
Q
V
V
D
D
R
R
660
|
Y
Y
I
I
A
A
S
S
E
E
V
V
C
C
E
E
D
D
S
S
670
|
I
I
T
T
V
V
G
G
M
M
V
V
R
R
H
H
Q
Q
G
G
680
|
K
K
I
I
M
M
Y
Y
V
V
G
G
D
D
V
V
R
R
S
S
690
|
V
V
T
T
Q
Q
K
K
H
H
I
I
Q
Q
E
E
W
W
G
G
700
|
P
P
F
F
D
D
L
L
V
V
I
I
G
G
G
G
S
S
P
P
710
|
C
C
N
N
D
D
L
L
S
S
I
I
V
V
N
N
P
P
A
A
720
|
R
R
K
K
G
G
L
L
Y
Y
E
E
G
G
T
T
G
G
R
R
730
|
L
L
F
F
F
F
E
E
F
F
Y
Y
R
R
L
L
L
L
H
H
740
|
D
D
A
A
R
R
P
P
K
K
E
E
G
G
D
D
D
D
R
R
750
|
P
P
F
F
F
F
W
W
L
L
F
F
E
E
N
N
V
V
V
V
760
|
A
A
M
M
G
G
V
V
S
S
D
D
K
K
R
R
D
D
I
I
770
|
S
S
R
R
F
F
L
L
E
E
S
S
N
N
P
P
V
V
M
M
780
|
I
I
D
D
A
A
K
K
E
E
V
V
S
S
A
A
A
A
H
H
790
|
R
R
A
A
R
R
Y
Y
F
F
W
W
G
G
N
N
L
L
P
P
800
|
G
G
M
M
N
N
R
R
P
P
L
L
A
A
S
S
T
T
V
V
810
|
N
N
D
D
K
K
L
L
E
E
L
L
Q
Q
E
E
C
C
L
L
820
|
E
E
H
H
G
G
R
R
I
I
A
A
K
K
F
F
S
S
K
K
830
|
V
V
R
R
T
T
I
I
T
T
T
T
R
R
S
S
N
N
S
S
840
|
I
I
K
K
Q
Q
G
G
K
K
D
D
Q
Q
H
H
F
F
P
P
850
|
V
V
F
F
M
M
N
N
E
E
K
K
E
E
D
D
I
I
L
L
860
|
W
W
C
C
T
T
E
E
M
M
E
E
R
R
V
V
F
F
G
G
870
|
F
F
P
P
V
V
H
H
Y
Y
T
T
D
D
V
V
S
S
N
N
880
|
M
M
S
S
R
H
L
L
A
A
R
R
Q
Q
R
R
L
L
L
L
890
|
G
G
R
R
S
S
W
W
S
S
V
V
P
P
V
V
I
I
R
R
900
|
H
H
L
L
F
F
A
A
P
P
L
L
K
K
E
E
Y
Y
F
F
910
|
A
A
C
C
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ADAM9/EGFR signaling pathway Inhibition hsa01521
AKT signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Next-generation sequencing assay
Mechanism Description DNMT3A mutations are most common in AML. DNMT3A mutant AML has been linked to anthracycline resistance and poor prognosis in some studies. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells.
Idarubicin
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Idarubicin
 Drug Info 
Molecule Alteration Missense mutation
p.R882H (c.2645G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 6W8B
Mutant Type Structure Method: X-ray diffraction Resolution: 2.44  Å
PDB: 6W8J
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.46
TM score: 0.99493
Amino acid change:
R882H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
A
A
E
E
630
|
K
K
R
R
K
K
P
P
I
I
R
R
V
V
L
L
S
S
L
L
640
|
F
F
D
D
G
G
I
I
A
A
T
T
G
G
L
L
L
L
V
V
650
|
L
L
K
K
D
D
L
L
G
G
I
I
Q
Q
V
V
D
D
R
R
660
|
Y
Y
I
I
A
A
S
S
E
E
V
V
C
C
E
E
D
D
S
S
670
|
I
I
T
T
V
V
G
G
M
M
V
V
R
R
H
H
Q
Q
G
G
680
|
K
K
I
I
M
M
Y
Y
V
V
G
G
D
D
V
V
R
R
S
S
690
|
V
V
T
T
Q
Q
K
K
H
H
I
I
Q
Q
E
E
W
W
G
G
700
|
P
P
F
F
D
D
L
L
V
V
I
I
G
G
G
G
S
S
P
P
710
|
C
C
N
N
D
D
L
L
S
S
I
I
V
V
N
N
P
P
A
A
720
|
R
R
K
K
G
G
L
L
Y
Y
E
E
G
G
T
T
G
G
R
R
730
|
L
L
F
F
F
F
E
E
F
F
Y
Y
R
R
L
L
L
L
H
H
740
|
D
D
A
A
R
R
P
P
K
K
E
E
G
G
D
D
D
D
R
R
750
|
P
P
F
F
F
F
W
W
L
L
F
F
E
E
N
N
V
V
V
V
760
|
A
A
M
M
G
G
V
V
S
S
D
D
K
K
R
R
D
D
I
I
770
|
S
S
R
R
F
F
L
L
E
E
S
S
N
N
P
P
V
V
M
M
780
|
I
I
D
D
A
A
K
K
E
E
V
V
S
S
A
A
A
A
H
H
790
|
R
R
A
A
R
R
Y
Y
F
F
W
W
G
G
N
N
L
L
P
P
800
|
G
G
M
M
N
N
R
R
P
P
L
L
A
A
S
S
T
T
V
V
810
|
N
N
D
D
K
K
L
L
E
E
L
L
Q
Q
E
E
C
C
L
L
820
|
E
E
H
H
G
G
R
R
I
I
A
A
K
K
F
F
S
S
K
K
830
|
V
V
R
R
T
T
I
I
T
T
T
T
R
R
S
S
N
N
S
S
840
|
I
I
K
K
Q
Q
G
G
K
K
D
D
Q
Q
H
H
F
F
P
P
850
|
V
V
F
F
M
M
N
N
E
E
K
K
E
E
D
D
I
I
L
L
860
|
W
W
C
C
T
T
E
E
M
M
E
E
R
R
V
V
F
F
G
G
870
|
F
F
P
P
V
V
H
H
Y
Y
T
T
D
D
V
V
S
S
N
N
880
|
M
M
S
S
R
H
L
L
A
A
R
R
Q
Q
R
R
L
L
L
L
890
|
G
G
R
R
S
S
W
W
S
S
V
V
P
P
V
V
I
I
R
R
900
|
H
H
L
L
F
F
A
A
P
P
L
L
K
K
E
E
Y
Y
F
F
910
|
A
A
C
C
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow N.A.
In Vivo Model NOD/SCID mouse xenograft model Mus musculus
Mechanism Description The missense mutation p.R882H (c.2645G>A) in gene DNMT3A cause the sensitivity of Idarubicin by unusual activation of pro-survival pathway
References
Ref 1 The role of mutations in epigenetic regulators in myeloid malignancies. Immunol Rev. 2015 Jan;263(1):22-35. doi: 10.1111/imr.12246.
Ref 2 Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin A single center experienceOncotarget. 2011 Nov;2(11):850-61. doi: 10.18632/oncotarget.347.

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