5v22
From Proteopedia
Crystal structure of human SETD2 SET-domain in complex with H3K36M peptide and SAH
Structural highlights
FunctionSETD2_HUMAN Histone methyltransferase that methylates 'Lys-36' of histone H3. H3 'Lys-36' methylation represents a specific tag for epigenetic transcriptional activation. Probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A. Binds DNA at promoters. May also act as a transcription activator that binds to promoters. Binds to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.[1] Publication Abstract from PubMedHistone H3 lysine 36 methylation (H3K36me) is critical for epigenetic regulation and mutations at or near H3K36 are associated with distinct types of cancers. H3K36M dominantly inhibits H3K36me on wild-type histones, whereas H3G34R/V selectively affects H3K36me on the same histone tail. Here we report the crystal structures of SETD2 SET domain in complex with an H3K36M peptide and SAM or SAH. There are large conformational changes in the substrate binding regions of the SET domain, and the K36M residue interacts with the catalytic pocket of SETD2. H3G34 is surrounded by a very narrow tunnel, which excludes larger amino acid side chains. H3P38 is in the trans configuration, and the cis configuration is incompatible with SETD2 binding. Finally, mutations of H3G34 or H3P38 alleviate the inhibitory effects of H3K36M on H3K36me, demonstrating that the stable interaction of H3K36M with SETD2 is critical for its inhibitory effects. Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation.,Zhang Y, Shan CM, Wang J, Bao K, Tong L, Jia S Sci Rep. 2017 Mar 3;7:43906. doi: 10.1038/srep43906. PMID:28256625[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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