Importance of Ile71 in β-actin on histidine methyltransferase SETD3 catalysis

Nurgül Bilgin, Laust Moesgaard, Marijn Maas, Jordi Hintzen, Apolonia Witecka, Jakub Drozak, Jacob Kongsted, Jasmin Mecinović*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


SETD3-catalysed N3-methylation of His73 in β-actin plays a key role in stabilisation of actin filaments in the metazoan cells. Overexpression and/or dysregulation of SETD3 is associated with several human pathologies, including cancer. Here, we examined the role of the Ile71 residue in β-actin on human SETD3 catalysis. Substitution of Ile71 in β-actin peptides by its natural and unnatural mimics reveals that the ‘secondary’ Ile71 binding pocket modulates the substrate efficiency of β-actin. Our enzymatic work demonstrates that human SETD3 can accommodate structurally diverse hydrophobic side chains in its Ile71 binding pocket, providing clear limits of the size and shape of Ile analogues. Water thermodynamics calculations reveal that the Ile71 pocket is occupied by high-energy water molecules, that are released upon the Ile71 binding, contributing favourably to the SETD3-βA complex formation. The work highlights that the hydrophobic Ile71 binding site plays an essential role in SETD3 catalysis, contributing to an ongoing effort in the design and development of chemical probes targeting SETD3.
Original languageEnglish
Article number1723
JournalOrganic & Biomolecular Chemistry
Issue number8
Pages (from-to)1723-1730
Number of pages8
Publication statusPublished - 28. Feb 2022


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