Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

KMT2A (Q03164) - Overview - Molecular Target Synopsis

Protein


KMT2A, Histone-lysine N-methyltransferase 2A
Enzyme Classification 2.1.1.43
UniProt Q03164

Also Known as KMT2A_HUMAN, KMT2A, ALL1, CXXC7, HRX, HTRX, MLL, MLL1, TRX1

Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation (PubMed:12453419, PubMed:20677832, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20677832, PubMed:20010842). Promotes PPP1R15A-induced apoptosis. Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-ARNTL/BMAL1 heterodimer. Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-ARNTL/BMAL1 to chromatin. MLL cleavage product N320 heterodimerizes with MLL cleavage product C180 (via SET and FYRC domains). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, HCFC2, WDR5, DPY30 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15199122, PubMed:15960975, PubMed:17500065, PubMed:19556245, PubMed:19187761, PubMed:26886794). Interacts with WDR5; the interaction is direct (PubMed:19556245, PubMed:18829459). Interaction with WDR5 is required for stable interaction with ASH2L and RBBP5, and thereby also for optimal histone methyltransferase activity (PubMed:26886794). Interacts with KAT8/MOF; the interaction is direct (PubMed:15960975). Interacts with SBF1 and PPP1R15A (PubMed:9537414, PubMed:10490642). Interacts with ZNF335 (PubMed:23178126). Interacts with CLOCK and ARNTL/BMAL1 in a circadian manner (By similarity). Interacts with PPIE; this results in decreased histone H3 methyltransferase activity (PubMed:20677832, PubMed:20541251). Interacts with CREBBP (PubMed:16253272).

2W5Z
TERNARY COMPLEX OF THE MIXED LINEAGE LEUKAEMIA (MLL1) SET DOMAIN WITH THE COFACTOR PRODUCT S-ADENOSYLHOMOCYSTEINE AND HISTONE PEPTIDE.
RCSB/PDB
Inspect Structure
See all 3D Structures for KMT2A

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: KMT2A is active in the following subcellular-locations: nucleus.
GO terms: KMT2A is active in the following subcellular-locations: cytosol, histone methyltransferase complex, MLL1 complex, nucleoplasm, nucleus.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project KMT2A has gain in 3 cell-lines, loss in 4 cell-lines and no signal in 998 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are:

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SF268, 143B, PANC-1

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: K562, SK-N-SH, MCF-7

(see details)

3D Structures


For KMT2A there are:
27 structures (32 chains) solved
4 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


KMT2A has been screened with 66 compounds (67 bioactivities), 52 compounds have bioactivities that show binding affinity of <= 500nM (52 bioactivities). (see details)