Top ▲

DOT1 like histone lysine methyltransferase

Click here for help

Target not currently curated in GtoImmuPdb

Target id: 2650

Nomenclature: DOT1 like histone lysine methyltransferase

Family: 2.1.1.43 Histone methyltransferases (HMTs)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1537 19p13.3 DOT1L DOT1 like histone lysine methyltransferase
Mouse - 1540 10 C1 Dot1l DOT1-like, histone H3 methyltransferase (S. cerevisiae)
Rat - 1549 7q11 Dot1l DOT1 like histone lysine methyltransferase
Previous and Unofficial Names Click here for help
disruptor of telomeric silencing 1-like | DOT1-like | DOT1-like histone H3K79 methyltransferase | DOT1 like histone H3K79 methyltransferase | DOT1-like, histone H3 methyltransferase (S. cerevisiae) | KMT4
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of DOT1L in complex with EPZ-5676.
PDB Id:  4HRA
Ligand:  pinometostat
Resolution:  3.15Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of DOT1L in complex with EPZ004777.
PDB Id:  4EK1
Ligand:  EPZ004777
Resolution:  2.85Å
Species:  Human
References:  1
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human DOT1L in complex with inhibitor SGC0946.
PDB Id:  4ER6
Ligand:  SGC0946
Resolution:  2.3Å
Species:  Human
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  DOT1L Structure in complex with S-adenosyl methionine (SAM, a cosubstrate involved in methyl group transfers)
PDB Id:  3QOW
Ligand:  S-adenosyl methionine   This ligand is endogenous
Resolution:  2.1Å
Species:  Human
References:  7

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
pinometostat Small molecule or natural product Ligand has a PDB structure Hs Inhibition 10.1 pKi 3
pKi 10.1 (Ki 8x10-11 M) [3]
compound 13 [Chen et al., 2016] Small molecule or natural product Hs Inhibition 10.1 pKi 2
pKi 10.1 (Ki 8x10-11 M) [2]
Description: Scintillation proximity assay result
bromo-deaza-SAH Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pKi 10
pKi 7.4 (Ki 3.8x10-8 M) [10]
SGC0946 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.5 pIC50 9
pIC50 9.5 (IC50 3x10-10 M) [9]
EPZ004777 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.4 pIC50 4
pIC50 9.4 (IC50 4x10-10 M) [4]
bromo-deaza-SAH Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.1 pIC50 10
pIC50 7.1 (IC50 7.7x10-8 M) [10]
Physiological Functions Click here for help
Under physiological conditions, Dot1L is critical for normal hematopoiesis.
Species:  Mouse
Tissue: 
References:  5-6
Physiological Consequences of Altering Gene Expression Click here for help
Dot1l knockout mice show that Dot1l is essential for embryonic development and prenatal hematopoiesis.
Species:  Mouse
Tissue: 
Technique:  Constitutive gene-knockout
References:  6
conditional deletion Dot1l postnatally leads to pancytopenia and failure of hematopoietic homeostasis.
Species:  Mouse
Tissue: 
Technique:  Conditional gene-knockout
References:  6
General Comments
DOT1L is the only known enzyme to methylate lysine 79 of histone 3 (H3K79), an epigenetic mark associated with active transcription.
DOT1L interacts with translocation partners of the mixed lineage leukemia (MLL) gene, KMT2A, and several MLL oncogenic fusion proteins that are commonly found in human leukemia aberrantly recruit Dot1L to ectopic loci. This causes local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. DOT1L has become a promising drug target for the development of pharmacological inhibitors with potential to treat MLL, which currently has limited treatment options and a very poor prognosis.

References

Show »

1. Basavapathruni A, Jin L, Daigle SR, Majer CR, Therkelsen CA, Wigle TJ, Kuntz KW, Chesworth R, Pollock RM, Scott MP et al.. (2012) Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Des, 80 (6): 971-80. [PMID:22978415]

2. Chen C, Zhu H, Stauffer F, Caravatti G, Vollmer S, Machauer R, Holzer P, Möbitz H, Scheufler C, Klumpp M et al.. (2016) Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach. ACS Med Chem Lett, 7 (8): 735-40. [PMID:27563395]

3. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP et al.. (2013) Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood, 122 (6): 1017-25. [PMID:23801631]

4. Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y et al.. (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell, 20 (1): 53-65. [PMID:21741596]

5. Feng Y, Yang Y, Ortega MM, Copeland JN, Zhang M, Jacob JB, Fields TA, Vivian JL, Fields PE. (2010) Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood, 116 (22): 4483-91. [PMID:20798234]

6. Jo SY, Granowicz EM, Maillard I, Thomas D, Hess JL. (2011) Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood, 117 (18): 4759-68. [PMID:21398221]

7. Richon VM, Johnston D, Sneeringer CJ, Jin L, Majer CR, Elliston K, Jerva LF, Scott MP, Copeland RA. (2011) Chemogenetic analysis of human protein methyltransferases. Chem Biol Drug Des, 78 (2): 199-210. [PMID:21564555]

8. Wernimont AK, Tempel W, Yu W, Scopton A, Li Y, Nguyen KT, Vedadi M, Bradner JE, Schapira M, Arrowsmith CH, Edwards AM, Bountra C et al. Crystal structure of human DOT1L in complex with inhibitor SGC0946. , Unpublished- DOI:10.2210/pdb4er6/pdb.

9. Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J et al.. (2012) Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun, 3: 1288. [PMID:23250418]

10. Yu W, Smil D, Li F, Tempel W, Fedorov O, Nguyen KT, Bolshan Y, Al-Awar R, Knapp S, Arrowsmith CH et al.. (2013) Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg. Med. Chem., 21 (7): 1787-94. [PMID:23433670]

How to cite this page

2.1.1.43 Histone methyltransferases (HMTs): DOT1 like histone lysine methyltransferase. Last modified on 16/08/2018. Accessed on 24/10/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2650.