Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

Shuang Yang, Xiangdong Zheng, Chao Lu, Guo Min Li, C. David Allis, Haitao Li

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylho-mocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2.

Original languageEnglish (US)
Pages (from-to)1611-1616
Number of pages6
JournalGenes and Development
Issue number14
StatePublished - Jul 15 2016


  • Crystal structure
  • Epigenetic regulation
  • Oncohistone
  • SETD2 methyltransferase

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


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