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A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Fagan, Vincent, Johansson, Catrine, Gileadi, Carina, Monteiro, Octovia, Dunford, James Edward, Nibhani, Reshma, Philpott, Martin, Malzahn, Jessica, Wells, Graham, Farham, Ruth, Cribbs, Adam, Halidi, Nadia, Li, Fengling, Chau, Irene, Greschik, Holger, Velupillai, Srikannathasan, Allali-Hassani, Abdellah, Bennett, James M, Christott, Thomas, Giroud, Charline, Lewis, Andrew M ORCID logoORCID: https://orcid.org/0000-0002-6447-354X, Huber, Kilian VM, Athanasou, Nick, Bountra, Chas, Jung, Manfred, Schüle, Roland, Vedadi, Masoud, Arrowsmith, Cheryl H, Xiong, Yan, Jin, Jian, Fedorov, Oleg, Farnie, Gillian, Brennan, Paul E and Oppermann, Udo CT (2019) A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function. Journal of Medicinal Chemistry, 62 (20). pp. 9008-9025. ISSN 0022-2623

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Abstract

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.

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