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Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase
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. H...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973290/ https://www.ncbi.nlm.nih.gov/pubmed/27474439 http://dx.doi.org/10.1101/gad.284323.116 |
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author | Yang, Shuang Zheng, Xiangdong Lu, Chao Li, Guo-Min Allis, C. David Li, Haitao |
author_facet | Yang, Shuang Zheng, Xiangdong Lu, Chao Li, Guo-Min Allis, C. David Li, Haitao |
author_sort | Yang, Shuang |
collection | PubMed |
description | 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-adenosylhomocysteine). 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. |
format | Online Article Text |
id | pubmed-4973290 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-49732902017-01-15 Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase Yang, Shuang Zheng, Xiangdong Lu, Chao Li, Guo-Min Allis, C. David Li, Haitao Genes Dev Research Communication 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-adenosylhomocysteine). 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. Cold Spring Harbor Laboratory Press 2016-07-15 /pmc/articles/PMC4973290/ /pubmed/27474439 http://dx.doi.org/10.1101/gad.284323.116 Text en © 2016 Yang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Communication Yang, Shuang Zheng, Xiangdong Lu, Chao Li, Guo-Min Allis, C. David Li, Haitao Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title | Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title_full | Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title_fullStr | Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title_full_unstemmed | Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title_short | Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase |
title_sort | molecular basis for oncohistone h3 recognition by setd2 methyltransferase |
topic | Research Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973290/ https://www.ncbi.nlm.nih.gov/pubmed/27474439 http://dx.doi.org/10.1101/gad.284323.116 |
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