Histone Lysine Methyltransferase SET7/9

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The C-terminal domain of lysine methyltransferase consists of a β-hairpin and α-helix that serve as a 'cap' for the SET domain. The overall structure of the <scene name='83/833386/C_terminal_domain/1'>C-terminal domain (residues 340-366)</scene> provides various interactions that facilitate binding of substrate to the SET domain (residues 193-344).<ref name="Xiao" /> Hydrophobic interactions between the C-terminal domain and the SET domain are mainly responsible in forming the access channel for the substrate and assist in deprotonation of the lysine. Residues 337-349 create a pro-gly rich <scene name='83/833386/Beta-hairpin/5'>β-hairpin</scene> that stabilizes the orientation of two tyrosine residues, Tyr 335 and Tyr337, that form the lysine access channel. Furthermore, there is substantial hydrophobic packing of the C-terminal helix against the SET domain using <scene name='83/833386/C_terminal_domain/4'>residues Phe299, Tyr353, Leu357 and Phe360 </scene>. These interactions position the indole ring of Trp352 in the C-terminal helix to <scene name='83/833386/C_terminal_domain/6'>stack with the π-cloud of the adenine base of the SAM co-factor</scene> as well as allowing Glu356 to hydrogen bond with N6 of the adenine ring.<ref name="Xiao" />[[Image:KMT_mechanism_final.png|800px|center|thumb|Figure 4: The proposed KMT Mechanism. The lysine substrate and transferred methyl group are in red.]]
The C-terminal domain of lysine methyltransferase consists of a β-hairpin and α-helix that serve as a 'cap' for the SET domain. The overall structure of the <scene name='83/833386/C_terminal_domain/1'>C-terminal domain (residues 340-366)</scene> provides various interactions that facilitate binding of substrate to the SET domain (residues 193-344).<ref name="Xiao" /> Hydrophobic interactions between the C-terminal domain and the SET domain are mainly responsible in forming the access channel for the substrate and assist in deprotonation of the lysine. Residues 337-349 create a pro-gly rich <scene name='83/833386/Beta-hairpin/5'>β-hairpin</scene> that stabilizes the orientation of two tyrosine residues, Tyr 335 and Tyr337, that form the lysine access channel. Furthermore, there is substantial hydrophobic packing of the C-terminal helix against the SET domain using <scene name='83/833386/C_terminal_domain/4'>residues Phe299, Tyr353, Leu357 and Phe360 </scene>. These interactions position the indole ring of Trp352 in the C-terminal helix to <scene name='83/833386/C_terminal_domain/6'>stack with the π-cloud of the adenine base of the SAM co-factor</scene> as well as allowing Glu356 to hydrogen bond with N6 of the adenine ring.<ref name="Xiao" />[[Image:KMT_mechanism_final.png|800px|center|thumb|Figure 4: The proposed KMT Mechanism. The lysine substrate and transferred methyl group are in red.]]
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==Inhibitors==
==Inhibitors==
SET7/9’s structure and function has been studied extensively because of its role in transcription <ref name="Takemoto">PMID:27088648</ref>. In the past few years it has been identified to methylate genes involved in multiple diseases; making it a potential candidate for drug inhibition.<ref name="Tamura">PMID:29723250</ref> Two compounds that have been found to inhibit SET7/9 in certain cells in vitro are Sinefungin and Cyproheptadine. Each inhibitor acts on the catalytic center of SET7/9, however their mechanisms of inhibition and possible medical relevancies differ greatly.
SET7/9’s structure and function has been studied extensively because of its role in transcription <ref name="Takemoto">PMID:27088648</ref>. In the past few years it has been identified to methylate genes involved in multiple diseases; making it a potential candidate for drug inhibition.<ref name="Tamura">PMID:29723250</ref> Two compounds that have been found to inhibit SET7/9 in certain cells in vitro are Sinefungin and Cyproheptadine. Each inhibitor acts on the catalytic center of SET7/9, however their mechanisms of inhibition and possible medical relevancies differ greatly.

Revision as of 17:07, 3 August 2020

SET7/9, A Histone Lysine Methyltransferase and epigenetic activator of transcription

Lysine Methyl Transferase

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Lauren Allman, Lauryn Padgett, Alexandra Pentala, Madeleine Wilson

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Mark Macbeth, Michal Harel, Valentine J Klimkowski, Angel Herraez

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