Identification of a peptide inhibitor for the histone methyltransferase WHSC1.
WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery targe...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5942779?pdf=render |
| _version_ | 1819231265283375104 |
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| author | Michael J Morrison P Ann Boriack-Sjodin Kerren K Swinger Tim J Wigle Dipti Sadalge Kevin W Kuntz Margaret Porter Scott William P Janzen Richard Chesworth Kenneth W Duncan Darren M Harvey John W Lampe Lorna H Mitchell Robert A Copeland |
| author_facet | Michael J Morrison P Ann Boriack-Sjodin Kerren K Swinger Tim J Wigle Dipti Sadalge Kevin W Kuntz Margaret Porter Scott William P Janzen Richard Chesworth Kenneth W Duncan Darren M Harvey John W Lampe Lorna H Mitchell Robert A Copeland |
| author_sort | Michael J Morrison |
| collection | DOAJ |
| description | WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease. |
| first_indexed | 2024-12-23T11:42:13Z |
| format | Article |
| id | doaj.art-5a738d78cc0446bf85ca79bb119bc45d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T11:42:13Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5a738d78cc0446bf85ca79bb119bc45d2022-12-21T17:48:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019708210.1371/journal.pone.0197082Identification of a peptide inhibitor for the histone methyltransferase WHSC1.Michael J MorrisonP Ann Boriack-SjodinKerren K SwingerTim J WigleDipti SadalgeKevin W KuntzMargaret Porter ScottWilliam P JanzenRichard ChesworthKenneth W DuncanDarren M HarveyJohn W LampeLorna H MitchellRobert A CopelandWHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.http://europepmc.org/articles/PMC5942779?pdf=render |
| spellingShingle | Michael J Morrison P Ann Boriack-Sjodin Kerren K Swinger Tim J Wigle Dipti Sadalge Kevin W Kuntz Margaret Porter Scott William P Janzen Richard Chesworth Kenneth W Duncan Darren M Harvey John W Lampe Lorna H Mitchell Robert A Copeland Identification of a peptide inhibitor for the histone methyltransferase WHSC1. PLoS ONE |
| title | Identification of a peptide inhibitor for the histone methyltransferase WHSC1. |
| title_full | Identification of a peptide inhibitor for the histone methyltransferase WHSC1. |
| title_fullStr | Identification of a peptide inhibitor for the histone methyltransferase WHSC1. |
| title_full_unstemmed | Identification of a peptide inhibitor for the histone methyltransferase WHSC1. |
| title_short | Identification of a peptide inhibitor for the histone methyltransferase WHSC1. |
| title_sort | identification of a peptide inhibitor for the histone methyltransferase whsc1 |
| url | http://europepmc.org/articles/PMC5942779?pdf=render |
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