9N39

DNA gyrase complexed with uncleaved DNA and Compound 185 to 2.25 A resolution

This is a non-PDB format compatible entry.

Summary for 9N39

• Entry DOI: 10.2210/pdb9n39/pdb
• Related: 9N26
• Descriptor: DNA gyrase subunit B fusion with DNA gyrase subunit A, DNA (5'-D(P*AP*GP*CP*CP*GP*TP*AP*GP*GP*GP*CP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: bacterial dna gyrase, inhibitor, nbti, dna binding protein
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 4
• Total formula weight: 169177.38

Authors

Bell, C.E.,McElroy, C.A.,Ratigan, S.C. (deposition date: 2025-01-30, release date: 2025-04-09, Last modification date: 2025-04-30)

Primary citation

Toth, P.D.,Ratigan, S.C.,Powell, J.W.,Cassel, S.R.,Yalowich, J.C.,McElroy, C.A.,Lindert, S.,Bell, C.E.,Mitton-Fry, M.J.
Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors.
Acs Med.Chem.Lett., 16:660-667, 2025

PubMed Abstract: Novel bacterial topoisomerase inhibitors (NBTIs) targeting DNA gyrase and topoisomerase IV constitute a new antibacterial class for deadly pathogens such as MRSA. While most NBTIs induce gyrase-mediated single-strand DNA breaks, a subset of amide NBTIs induces both single-strand and double-strand DNA breaks. Here, we report the X-ray crystal structures of two such amide NBTIs, and , and demonstrate an unusual binding mode characterized by engagement of both GyrA D83 and R122. The synthesis of two isosteric triazole NBTIs is also described, one of which () affords only single-strand DNA breaks, while the other () also induces both single- and double-strand DNA breaks. A combination of docking and molecular dynamics simulations is employed to further investigate the potential structural underpinnings of differences in DNA cleavage.

PubMed: 40248158
DOI: 10.1021/acsmedchemlett.5c00060

Experimental method

X-RAY DIFFRACTION (2.255 Å)