@article{4fc6e59821d04e2ca57ccbd4f35cf793,
title = "Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase",
abstract = "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.",
keywords = "Crystal structure, Epigenetic regulation, Oncohistone, SETD2 methyltransferase",
author = "Shuang Yang and Xiangdong Zheng and Chao Lu and Li, {Guo Min} and Allis, {C. David} and Haitao Li",
note = "Funding Information: We thank the staff at beamline BL17U of the Shanghai Synchrotron Radiation Facility and Dr. S. Fan at Tsinghua Center for Structural Biology for assistance in data collection. We thank the Center of Biomedical Analysis in Tsinghua University for providing isotope facilities. This work was supported by grants from the Ministry of Science and Technology of China (2016YFA0500700 and 2015CB910503) and the Tsinghua University Initiative Scientific Research Program to H.L., and funds from Rockefeller University and National Institutes of Health grant (P01CA196539) to C.D.A. C.L. is the Kandarian Family Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2195-14). H.L. conceived the study. S.Y. designed and performed the experiments with help from X.Z. and C.L. under the guidance of H.L. G.-M.L. and C.D.A. provided critical comments, and H.L. and S.Y. wrote the manuscript with input from the other authors. All authors reviewed the results and approved the final version of the manuscript. Publisher Copyright: {\textcopyright} 2016 Yang et al.",
year = "2016",
month = jul,
day = "15",
doi = "10.1101/gad.284323.116",
language = "English (US)",
volume = "30",
pages = "1611--1616",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "14",
}