An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors
Abstract
Polycomb repressive complex 2 (PRC2) mediates trimethylation of histone H3K27 (H3K27me3), an epigenetic hallmark for repressed chromatin. Overactive mutants of the histone lysine methyltransferase subunit of PRC2, Ezh2, are found in various types of cancers. Pyridone-containing inhibitors such as GSK126 compete with S-adenosylmethionine (SAM) for Ezh2 binding and effectively inhibit PRC2 activity. PRC2 from the thermophilic fungus Chaetomium thermophilum (ct) is functionally similar to the human version in several regards and has the added advantage of producing high-resolution crystal structures, although inhibitor-bound structures of human or human/chameleon PRC2 are also available at up to 2.6 Å resolution. We solved crystal structures of both human and ctPRC2 bound to GSK126 and the structurally similar inhibitor GSK343. While the two organisms feature a disparate degree of inhibitor potency, surprisingly, GSK126 binds in a similar manner in both structures. Structure-guided protein engineering of the drug binding pocket allowed us to introduce humanizing mutations into ctEzh2 to produce a ctPRC2 variant that is more susceptible to GSK126 inhibition. Additional analysis indicated that an evolutionarily conserved structural platform dictates a unique mode of GSK126 binding, suggesting a mechanism of drug selectivity. The existing drug scaffold may thus be used to probe the function and cellularmore »
- Authors:
-
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
- Sponsoring Org.:
- Welch Foundation; Cancer Prevention and Research Institute of Texas (CPRIT); Rita Allen Foundation; UT Southwestern Medical Center Endowed Scholar Fund; National Institutes of Health (NIH); Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research; USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of General Medical Sciences (NIGMS)
- OSTI Identifier:
- 1511727
- Grant/Contract Number:
- I-1790; R1119; GM114576; GM121662; AC02-06CH11357; AC02-76SF00515
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Histone post-translational modifications; Small molecules; X-ray crystallography
Citation Formats
Bratkowski, Matthew, Yang, Xin, and Liu, Xin. An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors. United States: N. p., 2018.
Web. doi:10.1038/s41598-018-27175-w.
Bratkowski, Matthew, Yang, Xin, & Liu, Xin. An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors. United States. https://doi.org/10.1038/s41598-018-27175-w
Bratkowski, Matthew, Yang, Xin, and Liu, Xin. Thu .
"An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors". United States. https://doi.org/10.1038/s41598-018-27175-w. https://www.osti.gov/servlets/purl/1511727.
@article{osti_1511727,
title = {An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors},
author = {Bratkowski, Matthew and Yang, Xin and Liu, Xin},
abstractNote = {Polycomb repressive complex 2 (PRC2) mediates trimethylation of histone H3K27 (H3K27me3), an epigenetic hallmark for repressed chromatin. Overactive mutants of the histone lysine methyltransferase subunit of PRC2, Ezh2, are found in various types of cancers. Pyridone-containing inhibitors such as GSK126 compete with S-adenosylmethionine (SAM) for Ezh2 binding and effectively inhibit PRC2 activity. PRC2 from the thermophilic fungus Chaetomium thermophilum (ct) is functionally similar to the human version in several regards and has the added advantage of producing high-resolution crystal structures, although inhibitor-bound structures of human or human/chameleon PRC2 are also available at up to 2.6 Å resolution. We solved crystal structures of both human and ctPRC2 bound to GSK126 and the structurally similar inhibitor GSK343. While the two organisms feature a disparate degree of inhibitor potency, surprisingly, GSK126 binds in a similar manner in both structures. Structure-guided protein engineering of the drug binding pocket allowed us to introduce humanizing mutations into ctEzh2 to produce a ctPRC2 variant that is more susceptible to GSK126 inhibition. Additional analysis indicated that an evolutionarily conserved structural platform dictates a unique mode of GSK126 binding, suggesting a mechanism of drug selectivity. The existing drug scaffold may thus be used to probe the function and cellular regulation of PRC2 in a wide spectrum of organisms, ranging from fungi to humans.},
doi = {10.1038/s41598-018-27175-w},
journal = {Scientific Reports},
number = 1,
volume = 8,
place = {United States},
year = {Thu Jun 14 00:00:00 EDT 2018},
month = {Thu Jun 14 00:00:00 EDT 2018}
}
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Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2
journal, September 2012
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journal, April 2016
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Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance
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Structure of the Catalytic Domain of EZH2 Reveals Conformational Plasticity in Cofactor and Substrate Binding Sites and Explains Oncogenic Mutations
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Structural Context of Disease-Associated Mutations and Putative Mechanism of Autoinhibition Revealed by X-Ray Crystallographic Analysis of the EZH2-SET Domain
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Works referencing / citing this record:
Polycomb repressive 2 complex—Molecular mechanisms of function
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PRC2 is high maintenance
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