Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin.

ABSTRACT: Actin histidine N^τ -methylation by histidine methyltransferase SETD3 plays an important role in human biology and diseases. Here, we report integrated synthetic, biocatalytic, biostructural, and computational analyses on human SETD3-catalyzed methylation of actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N-nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical molecular dynamics and free-energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data tha

SUBMITTER: Hintzen JCJ 

PROVIDER: S-EPMC9004244 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature