Histone methyltransferase: Difference between revisions

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<StructureSection load='1o9s' size='450' side='right' caption='Human histone-lysine N-methyltrasferase (magenta) complex with methylated lysine histone H3 peptide (green) and S-adenosyl homocysteine (SAH) (PDB entry [[1o9s]])' scene='46/467278/Cv/1'>
<StructureSection load='' size='350' side='right' caption='Human histone-lysine N-methyltrasferase (magenta) complex with methylated lysine histone H3 peptide (green) and S-adenosyl homocysteine (SAH) (PDB entry [[1o9s]])' scene='46/467278/Cv/1'>


== Function ==
== 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<ref>PMID:15248813</ref>.  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.
'''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<ref>PMID:15248813</ref>.  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.
For SET7/9 see [[Histone Lysine Methyltransferase SET7/9]].
*'''euchromatin histone methyltransferase''' dimethylates histone H3 at Lys 9 resulting in transcriptional repression<ref>PMID:32684241</ref>.
*'''DOT1L histone methyltransferase''' methylates histone H3 at Lys 79 resulting in transcriptional repression<ref>PMID:35495127</ref>.


== Relevance ==
== Relevance ==
Line 11: Line 16:


== Structural highlights ==
== Structural highlights ==
Human <scene name='46/467278/Cv/5'>KHMT binds SAH in the peptide binding groove with the histone H3 peptide assuming an extended conformation and the methylated lysine</scene> inserted in a hydrophobic environment<ref>PMID:12540855</ref>. Water molecules shown as red spheres
Human <scene name='46/467278/Cv/6'>KHMT binds SAH in the peptide binding groove with the histone H3 peptide assuming an extended conformation and the methylated lysine</scene> inserted in a hydrophobic environment<ref>PMID:12540855</ref>. Water molecules shown as red spheres
</StructureSection>


== 3D Structures of histone methyltransferase ==
== 3D Structures of histone methyltransferase ==  
[[Histone methyltransferase 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*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<br />
**[[2mdc]], [[2mdj]] - hKHMT SETD2 WW domain - NMR<br />
**[[2mdi]] - hKHMT SETD2 WW domain (mutant) - NMR<br />
**[[2r3a]] – hKHMT Suv39H2<br />
**[[3rq4]] - hKHMT Suv420H2<br />
**[[3s8p]] - hKHMT Suv420H1<br />
**[[3mts]] - hKHMT Suv39H1 chromo domain<br />
**[[1h3i]] - hKHMT SET7/9 residues 52-344<br />
**[[2o8j]] - hKHMT H3K9 residues 913-1193<br />
**[[2lv9]] - hKHMT Mll5 residues 109-188 - NMR<br />
**[[2kyu]] - hKHMT Mll Phd3 finger – NMR<br />
**[[4gnd]] - hKHMT Nsd3 Phd5-C5HCH<br />
**[[4rxj]] - hKHMT Nsd3 residues 953-1064<br />
**[[4yz8]] - hKHMT Nsd3 residues 1054-1285<br />
**[[3lqh]] - hKHMT Mll Phd bromodomain<br />
**[[3b7b]] - hKHMT ankyrin repeat domains 2-7<br />
**[[3bo5]] – hKHMT Setmar methyltransferase domain <br />
**[[3k9j]], [[3k9k]] – hKHMT Setmar transposable domain (mutant)<br />
**[[3dlm]] - hKHMT Setmdb1 Tudor domain <br />
**[[3n71]] - hKHMT Smyd1<br />
**[[3rsn]], [[3s32]] – hKHMT Ash2 N terminal<br />
**[[3toj]] – hKHMT Ash2 Spry domain<br />
**[[4ijd]] – hKHMT Prdm9<br />
**[[4mi0]] – hKHMT Ezh2<br />
**[[4mi5]] – hKHMT Ezh2 SET domain<br />
**[[1ml9]] – NcKHMT Dim-5 – ''Neurospora crassa''<br />
**[[1n3j]] – PvKHMT – Paramecium bursaria chlorella virus<br />
**[[1u2z]] – yKHMT C terminal<br />
**[[2l7p]] – AtKHMT Ashh2 CW domain – ''Arabidopsis thaliana'' - NMR<br />
**[[2lxe]] – AtKHMT Suvr4 SET31 - NMR<br />
 
*Histone-lysine N-methyltransferase binary complexes
 
**[[2kkf]] – hKHMT Hrx CxxC domain + DNA – NMR<br />
**[[4nw3]] – hKHMT Mll CxxC domain + DNA <br />
**[[4pzi]] – hKHMT CxxC domain + DNA <br />
**[[3q0b]], [[3q0c]], [[3q0d]], [[3q0f]] – hKHMT SRA domain + DNA <br />
**[[3qow]] – hKHMT + SAM <br />
**[[4fmu]] – hKHMT SETD2 + inhibitor <br />
**[[4h12]] – hKHMT SETD2 + SAH <br />
**[[3smt]] – hKHMT SETD3 + SAM <br />
**[[4bup]], [[3ooi]] – hKHMT SET domain + SAM <br />
**[[3qox]], [[3sx0]] – hKHMT + SAH <br />
**[[3sr4]], [[3uwp]], [[4ek9]], [[4ekg]], [[4eki]], [[4eqz]], [[4er0]], [[4er3]], [[4er5]], [[4er6]], [[4er7]], [[4hra]] - hKHMT catalytic domain + inhibitor<br />
**[[2w5y]] – hKHMT Hrx methyltransferase domain + SAH <br />
**[[3f2k]] – hKHMT Setmar SET domain + LYFA peptide<br />
**[[3sw9]], [[3swc]] – hKHMT SET domain + peptide<br />
**[[4gne]], [[4gnf]], [[4gng]] - hKHMT Nsd3 Phd5-C5HCH + H3 peptide<br />
**[[3b95]] - hKHMT ankyrin repeat domain + H3 peptide<br />
**[[3lqi]], [[3lqj]] - hKHMT Mll1 3rd Phd finger and bromodomain + H3 peptide<br />
**[[3rib]] – hKHMT Smyd2 + SAH<br />
**[[3s7j]], [[3tg4]] - hKHMT Smyd2 + SAM<br />
**[[4wuy]] - hKHMT Smyd2 + inhibitor<br />
**[[1mt6]] - hKHMT SET7/9 residues 58-337 + SAH<br />
**[[1n6a]] – hKHMT SET7/9 SET domain + SAM<br />
**[[1n6c]] – hKHMT SET7/9 residues 70-366 + SAM<br />
**[[3cbp]] - hKHMT SET7/9 SET domain + sinefungin<br />
**[[3vuz]], [[3vv0]] - hKHMT SET7/9 SET domain + deoxyadenosine derivative<br />
**[[4l58]] - hKHMT PHD-type zinc finger domain + H3 peptide<br />
 
*Histone-lysine N-methyltransferase ternary complex
 
**[[2w5z]] – hKHMT Hrx methyltransferase domain + SAH + histone peptide<br />
**[[1o9s]] - hKHMT SET7/9 SET domain + SAH + H3 peptide<br />
**[[2bqz]] - hKHMT SET7 SET domain + SAH + H4 peptide<br />
**[[3f9w]], [[3f9x]], [[3f9y]], [[3f9z]] - hKHMT SETD8 SET domain + SAH + H4 peptide<br />
**[[4ij8]] - hKHMT SETD8 + SAM + H3 peptide<br />
**[[4j7i]], [[4j83]], [[4j8o]], [[4j7f]] - hKHMT SETD7 + SAH + TFIID peptide<br />
**[[3fpd]], [[3k5k]], [[3mo0]], [[3mo2]], [[3mo5]], [[3rjw]], [[4nvq]] - hKHMT SET domain + SAH + inhibitor<br />
**[[2rfi]], [[3hna]] - hKHMT H3K9 catalytic domain + SAH + H3 peptide<br />
**[[1xqh]] - hKHMT SET7/9 SET domain + SAH + p53 peptide<br />
**[[2f69]], [[3m53]] - hKHMT SET7/9 SZET domain + SAH + TAF10 peptide<br />
**[[3m54]], [[3m55]], [[3m56]], [[3m57]], [[3m58]], [[3m59]], [[3m5a]] - hKHMT SET7/9 SET domain (mutant) + SAH + TAF10 peptide<br />
**[[3cbm]] - hKHMT SET7/9 SET domain + SAM + estrogen receptor peptide<br />
**[[4e47]], [[4jds]], [[4jlg]] - hKHMT SET7/9 SET domain + SAM + inhibitor<br />
**[[3cbo]] - hKHMT SET7/9 SET domain + SAH + estrogen receptor peptide<br />
**[[3os5]] - hKHMT SET7/9 SET domain + SAH + DNMT1 peptide<br />
**[[3qxy]], [[3rc0]] - hKHMT SETD6 SET domain + p65 peptide + SAM<br />
**[[3s7b]] - hKHMT Smyd2 + SAM + inhibitor<br />
**[[3s7d]], [[3s7f]], [[3tg5]] - hKHMT Smyd2 + SAH + p53 peptide<br />
**[[4o6f]] – hKHMT Smyd2 (mutant) + SAH + estrogen receptor peptide<br />
**[[1zkk]] - hKHMT + SAH + H4 peptide <br />
**[[4c1q]] - hKHMT SET domain + SAH + H3 peptide <br />
**[[4i51]] - hKHMT (mutant) + SAH + H3 peptide <br />
**[[1peg]] - NcKHMT Dim-5 + SAH + H3 peptide<br />
**[[2g46]] – PvKHMT + SAH + H3 peptide<br />
**[[4au7]] - mKHMT + SAH + H4 peptide - mouse<br />
 
*Histone-arginine N-methyltransferase (Carm1)
 
**[[2v74]], [[2v7e]] – mRHMT catalytic domain <br />
**[[4c03]], [[4c06]], [[4c07]], [[4c08]] – mRHMT  6<br />
**[[4c04]] – mRHMT  6 + inhibitor<br />
**[[4c05]] – mRHMT  6 + SAH<br />
**[[4c4a]] – mRHMT  7 + SAH<br />
**[[2obq]] – rRHMT N terminal - rat <br />
**[[3b3g]], [[3b3j]] – rRHMT catalytic domain <br />
**[[3b3f]] – rRHMT catalytic domain + SAH<br />
**[[2y1w]], [[2y1x]] – hRHMT 4 catalytic domain + sinefungin + indole inhibitor<br />
**[[4ikp]] – hRHMT 4 catalytic domain + purine derivative<br />
**[[4gqb]] – hRHMT 5 + methylsome protein 50 + H4 peptide<br />
**[[4qqk]] – hRHMT 6 <br />
**[[4hc4]] – hRHMT 6 (mutant)<br />
**[[4qpp]] – hRHMT 6 (mutant) + peptide + inhibitor<br />


}}
== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Latest revision as of 11:47, 2 July 2024


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.

For SET7/9 see Histone Lysine Methyltransferase SET7/9.

  • euchromatin histone methyltransferase dimethylates histone H3 at Lys 9 resulting in transcriptional repression[2].
  • DOT1L histone methyltransferase methylates histone H3 at Lys 79 resulting in transcriptional repression[3].

Relevance

Inhibitors of the histone-lysine N-methyltransferase SMYD2 which represses the tumor-suppressing activities of p53 are studied as cancer therapy drugs[4].

Disease

Aberrant HMT plays a role in cancer, intellectual disability syndromes and regulation of tissue aging[5].

Structural highlights

Human inserted in a hydrophobic environment[6]. Water molecules shown as red spheres

3D Structures of histone methyltransferase

Histone methyltransferase 3D structures


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

ReferencesReferences

  1. ↑ Trievel RC. Structure and function of histone methyltransferases. Crit Rev Eukaryot Gene Expr. 2004;14(3):147-69. PMID:15248813
  2. ↑ Hwang S, Kim S, Kim K, Yeom J, Park S, Kim I. Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein. BMB Rep. 2020 Nov;53(11):576-581. PMID:32684241 doi:10.5483/BMBRep.2020.53.11.055
  3. ↑ Alexandrova E, Salvati A, Pecoraro G, Lamberti J, Melone V, Sellitto A, Rizzo F, Giurato G, Tarallo R, Nassa G, Weisz A. Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors. Front Genet. 2022 Apr 13;13:864612. PMID:35495127 doi:10.3389/fgene.2022.864612
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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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Michal Harel, Alexander Berchansky, Joel L. Sussman
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