DNA Binding Mechanism of The Virulence Regulator SarA in Staphylococcus aureus

Abstract

Staphylococcus aureus infections have long been a significant challenge to public health, particularly due to the emergence of multiple drug-resistant strains. SarA is a critical global regulator in S. aureus which binds to AT-rich sequences in the promoter regions of various genes, but the DNA-binding mechanism of SarA remains unclear. Here, we determined the solution structures of a monomeric DNA binding domain of SarA (SarA^ΔN19) and its complex with an AT-rich double-stranded DNA. The winged helix domain of SarA^ΔN19 binds to DNA in a classic way, with the α4 helix binding to the major groove of DNA, while the L5 loop binding to the minor groove, covering 10 AT base pairs. Residues L53, P65, and V68 of the α4 helix have hydrophobic interactions with thymine bases and sugar rings. The side chains of Arg90 and Arg84 from the wing are inserted into the minor groove, forming hydrogen bonds with A/T bases. Multiple positively charged or hydrophilic residues, including Lys54, Lys63, Lys69, Lys72, Lys82, and Gln64, interact with the phosphate groups on the DNA backbones. This complex structure provides an in-depth understanding of the molecular mechanism for SarA to bind DNA, and a better structure basis for future anti-bacterial drug design targeting SarA.