Histone methyltransferase

Function

Histone methyltransferase (HMT) are histone-lysine N-methyltransferase (KHMT) and histone-arginine N-methyltransferase (RHMT) which catalyzes the transfer of methyl groups to lysine and arginine residues of histones^[1]. HMT use S-adenosyl methionine (SAM) or S-adenosyl homocysteine (SAH) as the methyl donor. KHMT can be SET domain-containing or non-SET domain-containing. The SET domain contains the catalytic core of KHMT and targets the lysine tail region of KHMT. CxxC domain is a zinc finger domain.

Relevance

Inhibitors of the histone-lysine N-methyltransferase SMYD2 which represses the tumor-suppressing activities of p53 are studied as cancer therapy drugs^[2].

Disease

Aberrant HMT plays a role in cancer, intellectual disability syndromes and regulation of tissue aging^[3].

Structural highlights

Human KHMT binds SAH in the peptide binding groove with the histone H3 peptide assuming an extended conformation and the methylated lysine inserted in a hydrophobic environment^[4].

Human histone-lysine N-methyltrasferase (magenta) complex with methylated lysine histone H3 peptide (green) and S-adenosyl homocysteine (SAH) (PDB entry 1o9s)

Drag the structure with the mouse to rotate

3D Structures of histone methyltransferase3D Structures of histone methyltransferase

Updated on 03-April-2016

DOT1L histone methyltransferase
- 1nw3 – hHMT DOT1L – human
Euchromatic histone methyltransferase
- 2igq – hHMT-1 C terminal
Histone-lysine N-methyltransferase
- 2j8a – KHMT SET1 RRM domain – yeast
- 3s8s – hKHMT SETD1A RRM domain
- 2mdc, 2mdj - hKHMT SETD2 WW domain - NMR
- 2mdi - hKHMT SETD2 WW domain (mutant) - NMR
- 2r3a – hKHMT Suv39H2
- 3rq4 - hKHMT Suv420H2
- 3s8p - hKHMT Suv420H1
- 3mts - hKHMT Suv39H1 chromo domain
- 1h3i - hKHMT SET7/9 residues 52-344
- 2o8j - hKHMT H3K9 residues 913-1193
- 2lv9 - hKHMT Mll5 residues 109-188 - NMR
- 2kyu - hKHMT Mll Phd3 finger – NMR
- 4gnd - hKHMT Nsd3 Phd5-C5HCH
- 4rxj - hKHMT Nsd3 residues 953-1064
- 4yz8 - hKHMT Nsd3 residues 1054-1285
- 3lqh - hKHMT Mll Phd bromodomain
- 3b7b - hKHMT ankyrin repeat domains 2-7
- 3bo5 – hKHMT Setmar methyltransferase domain
- 3k9j, 3k9k – hKHMT Setmar transposable domain (mutant)
- 3dlm - hKHMT Setmdb1 Tudor domain
- 3n71 - hKHMT Smyd1
- 3rsn, 3s32 – hKHMT Ash2 N terminal
- 3toj – hKHMT Ash2 Spry domain
- 4ijd – hKHMT Prdm9
- 4mi0 – hKHMT Ezh2
- 4mi5 – hKHMT Ezh2 SET domain
- 1ml9 – NcKHMT Dim-5 – Neurospora crassa
- 1n3j – PvKHMT – Paramecium bursaria chlorella virus
- 1u2z – yKHMT C terminal
- 2l7p – AtKHMT Ashh2 CW domain – Arabidopsis thaliana - NMR
- 2lxe – AtKHMT Suvr4 SET31 - NMR
Histone-lysine N-methyltransferase binary complexes
- 2kkf – hKHMT Hrx CxxC domain + DNA – NMR
- 4nw3 – hKHMT Mll CxxC domain + DNA
- 4pzi – hKHMT CxxC domain + DNA
- 3q0b, 3q0c, 3q0d, 3q0f – hKHMT SRA domain + DNA
- 3qow – hKHMT + SAM
- 4fmu – hKHMT SETD2 + inhibitor
- 4h12 – hKHMT SETD2 + SAH
- 3smt – hKHMT SETD3 + SAM
- 4bup, 3ooi – hKHMT SET domain + SAM
- 3qox, 3sx0 – hKHMT + SAH
- 3sr4, 3uwp, 4ek9, 4ekg, 4eki, 4eqz, 4er0, 4er3, 4er5, 4er6, 4er7, 4hra - hKHMT catalytic domain + inhibitor
- 2w5y – hKHMT Hrx methyltransferase domain + SAH
- 3f2k – hKHMT Setmar SET domain + LYFA peptide
- 3sw9, 3swc – hKHMT SET domain + peptide
- 4gne, 4gnf, 4gng - hKHMT Nsd3 Phd5-C5HCH + H3 peptide
- 3b95 - hKHMT ankyrin repeat domain + H3 peptide
- 3lqi, 3lqj - hKHMT Mll1 3rd Phd finger and bromodomain + H3 peptide
- 3rib – hKHMT Smyd2 + SAH
- 3s7j, 3tg4 - hKHMT Smyd2 + SAM
- 4wuy - hKHMT Smyd2 + inhibitor
- 1mt6 - hKHMT SET7/9 residues 58-337 + SAH
- 1n6a – hKHMT SET7/9 SET domain + SAM
- 1n6c – hKHMT SET7/9 residues 70-366 + SAM
- 3cbp - hKHMT SET7/9 SET domain + sinefungin
- 3vuz, 3vv0 - hKHMT SET7/9 SET domain + deoxyadenosine derivative
- 4l58 - hKHMT PHD-type zinc finger domain + H3 peptide
Histone-lysine N-methyltransferase ternary complex
- 2w5z – hKHMT Hrx methyltransferase domain + SAH + histone peptide
- 1o9s - hKHMT SET7/9 SET domain + SAH + H3 peptide
- 2bqz - hKHMT SET7 SET domain + SAH + H4 peptide
- 3f9w, 3f9x, 3f9y, 3f9z - hKHMT SETD8 SET domain + SAH + H4 peptide
- 4ij8 - hKHMT SETD8 + SAM + H3 peptide
- 4j7i, 4j83, 4j8o, 4j7f - hKHMT SETD7 + SAH + TFIID peptide
- 3fpd, 3k5k, 3mo0, 3mo2, 3mo5, 3rjw, 4nvq - hKHMT SET domain + SAH + inhibitor
- 2rfi, 3hna - hKHMT H3K9 catalytic domain + SAH + H3 peptide
- 1xqh - hKHMT SET7/9 SET domain + SAH + p53 peptide
- 2f69, 3m53 - hKHMT SET7/9 SZET domain + SAH + TAF10 peptide
- 3m54, 3m55, 3m56, 3m57, 3m58, 3m59, 3m5a - hKHMT SET7/9 SET domain (mutant) + SAH + TAF10 peptide
- 3cbm - hKHMT SET7/9 SET domain + SAM + estrogen receptor peptide
- 4e47, 4jds, 4jlg - hKHMT SET7/9 SET domain + SAM + inhibitor
- 3cbo - hKHMT SET7/9 SET domain + SAH + estrogen receptor peptide
- 3os5 - hKHMT SET7/9 SET domain + SAH + DNMT1 peptide
- 3qxy, 3rc0 - hKHMT SETD6 SET domain + p65 peptide + SAM
- 3s7b - hKHMT Smyd2 + SAM + inhibitor
- 3s7d, 3s7f, 3tg5 - hKHMT Smyd2 + SAH + p53 peptide
- 4o6f – hKHMT Smyd2 (mutant) + SAH + estrogen receptor peptide
- 1zkk - hKHMT + SAH + H4 peptide
- 4c1q - hKHMT SET domain + SAH + H3 peptide
- 4i51 - hKHMT (mutant) + SAH + H3 peptide
- 1peg - NcKHMT Dim-5 + SAH + H3 peptide
- 2g46 – PvKHMT + SAH + H3 peptide
- 4au7 - mKHMT + SAH + H4 peptide - mouse
Histone-arginine N-methyltransferase (Carm1)
- 2v74, 2v7e – mRHMT catalytic domain
- 4c03, 4c06, 4c07, 4c08 – mRHMT 6
- 4c04 – mRHMT 6 + inhibitor
- 4c05 – mRHMT 6 + SAH
- 4c4a – mRHMT 7 + SAH
- 2obq – rRHMT N terminal - rat
- 3b3g, 3b3j – rRHMT catalytic domain
- 3b3f – rRHMT catalytic domain + SAH
- 2y1w, 2y1x – hRHMT 4 catalytic domain + sinefungin + indole inhibitor
- 4ikp – hRHMT 4 catalytic domain + purine derivative
- 4gqb – hRHMT 5 + methylsome protein 50 + H4 peptide
- 4qqk – hRHMT 6
- 4hc4 – hRHMT 6 (mutant)
- 4qpp – hRHMT 6 (mutant) + peptide + inhibitor

ReferencesReferences

↑ Trievel RC. Structure and function of histone methyltransferases. Crit Rev Eukaryot Gene Expr. 2004;14(3):147-69. PMID:15248813
↑ Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, Cheung T, Garcia-Arenas R, Cowen S, Wu J, Godin R, Chen H, Keen N. Structural Basis of Substrate Methylation and Inhibition of SMYD2. Structure. 2011 Jul 20. PMID:21782458 doi:10.1016/j.str.2011.06.011
↑ Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012 Apr 3;13(5):343-57. doi: 10.1038/nrg3173. PMID:22473383 doi:http://dx.doi.org/10.1038/nrg3173
↑ Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature. 2003 Feb 6;421(6923):652-6. Epub 2003 Jan 22. PMID:12540855 doi:10.1038/nature01378

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

[1] Trievel RC. Structure and function of histone methyltransferases. Crit Rev Eukaryot Gene Expr. 2004;14(3):147-69. PMID:15248813

[2] Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, Cheung T, Garcia-Arenas R, Cowen S, Wu J, Godin R, Chen H, Keen N. Structural Basis of Substrate Methylation and Inhibition of SMYD2. Structure. 2011 Jul 20. PMID:21782458 doi:10.1016/j.str.2011.06.011

[3] Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012 Apr 3;13(5):343-57. doi: 10.1038/nrg3173. PMID:22473383 doi:http://dx.doi.org/10.1038/nrg3173

[4] Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature. 2003 Feb 6;421(6923):652-6. Epub 2003 Jan 22. PMID:12540855 doi:10.1038/nature01378

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