β-Actin Peptide-Based Inhibitors of Histidine Methyltransferase SETD3

Jordi C J Hintzen, Laust Moesgaard, Sebastian Kwiatkowski, Jakub Drozak, Jacob Kongsted, Jasmin Mecinović*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

SETD3 was recently identified as the histidine methyltransferase responsible for N 3 -methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin peptide was found to be the most potent SETD3 inhibitor (IC 50 = 161 nM). Supporting our inhibition assays, a combination of computational docking and molecular dynamics simulations revealed that the His73 binding pocket for β-actin in SETD3 is rigid and accommodates the inhibitor peptides with similar binding modes. Collectively, our work demonstrates that actin-based peptidomimetics can act as potent SETD3 inhibitors and provide a basis for further development of highly potent and selective inhibitors of SETD3.

Original languageEnglish
JournalChemMedChem
Volume16
Issue number17
Pages (from-to)2695-2702
ISSN1860-7179
DOIs
Publication statusPublished - 6. Sep 2021

Bibliographical note

© 2021 Wiley-VCH GmbH.

Keywords

  • actin
  • histidine
  • methylation
  • peptidomimetics
  • protein-protein interactions

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