9SMZ
Structure of Staphylococcus aureus MarR-type repressor MhqR bound to MBQ
Summary for 9SMZ
| Entry DOI | 10.2210/pdb9smz/pdb |
| Related | 9QDR |
| Descriptor | MarR family transcriptional regulator, 2-methylcyclohexa-2,5-diene-1,4-dione (3 entities in total) |
| Functional Keywords | marr-type repressor, winged helix-turn-helix, dimer, dna binding protein |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 2 |
| Total formula weight | 35680.79 |
| Authors | |
| Primary citation | Nguyen, T.T.-.P.,Weiland, P.,Loi, V.V.,Kiontke, S.,Burchert, F.,Zegarra, V.,Kern, A.,Fritsch, V.N.,Baranov, D.,Bronowska, A.K.,Bange, G.,Antelmann, H. Structural basis of quinone sensing by the MarR-type repressor MhqR in Staphylococcus aureus. Mbio, :e0329225-e0329225, 2025 Cited by PubMed Abstract: The MarR-family regulator MhqR of (MhqR) was previously characterized as a quinone-sensing repressor of the operon. Here, we solved the crystal structures of apo-MhqR and the 2-methylbenzoquinone (MBQ)-bound MhqR complex. AlphaFold3 modeling was used to predict the structure of MhqR in complex with its operator DNA. In the DNA-bound MhqR state, S65 and S66 of an allosteric α3-α4 loop adopted a helically wound conformation to elongate helix α4 for optimal DNA binding. Key residues for MBQ interaction were identified as F11, F39, E43, and H111, forming the MBQ-binding pocket. MBQ binding prevented the formation of the extended helix α4 in the allosteric loop, leading to steric clashes with the DNA. Molecular dynamics (MD) simulations revealed an increased intrinsic dynamics within the allosteric loop and the β1/β2-wing regions after MBQ binding to prevent DNA binding. Using mutational analyses, we validated that F11, F39, and H111 are required for quinone sensing whereas S65 and S66 of the allosteric loop and D88, K89, V91, and Y92 of the β1/β2-wing are essential for DNA binding and . In conclusion, our structure-guided modeling and mutational analyses identified a quinone-binding pocket in MhqR and the mechanism of MhqR inactivation, which involves local structural rearrangements of an allosteric loop and high intrinsic dynamics to prevent DNA interactions. Our results provide novel insights into the redox mechanism of the conserved MhqR repressor, which functions as an important determinant of quinone and antimicrobial resistance in .IMPORTANCE is a major human pathogen that can cause life-threatening infections in humans. However, treatment options are limited due to the prevalence of antimicrobial-resistant isolates in the hospital and the community. The MarR-type repressor MhqR was described to control resistance toward quinones and quinone-like antimicrobials. However, the redox-regulatory mechanism of MhqR by quinones was unknown. In this work, we explored the DNA-binding and quinone-sensing mechanism of MhqR and identified a quinone-binding pocket and an allosteric loop, which facilitates DNA binding activity via a helical wound conformation and adapts an unstructured coiled conformation upon quinone binding to inhibit DNA binding. A similar mechanism has been recently discovered for the regulation of uric acid resistance by UrtR family repressors (W. S. Song, D. U. Ki , H. Y. Cho, O. H. Kwon, H. Cho, S. I. Yoon, Nucleic Acids Res 52:13192-13205, 2024, https://doi.org/10.1093/nar/gkae922). Our results contribute to a better understanding of antimicrobial resistance regulation, which may be exploited for future drug design to combat multidrug-resistant . PubMed: 41474324DOI: 10.1128/mbio.03292-25 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.28 Å) |
Structure validation
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