6Z1A

Ternary complex of Staphylococcus aureus DNA gyrase with AMK12 and DNA

Summary for 6Z1A

• Entry DOI: 10.2210/pdb6z1a/pdb
• Descriptor: DNA gyrase subunit B,DNA gyrase subunit A, DNA (5'-D(*AP*GP*CP*CP*GP*TP*AP*G)-3'), DNA (5'-D(P*GP*TP*AP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), ... (9 entities in total)
• Functional Keywords: type iia topoisomerase, antibacterial, inhibitor, isomerase, fusion protein
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 6
• Total formula weight: 169715.13

Authors

Kolaric, A.,Germe, T.,Hrast, M.,Stevenson, C.E.M.,Lawson, D.M.,Burton, N.,Voros, J.,Maxwell, A.,Minovski, N.,Anderluh, M. (deposition date: 2020-05-13, release date: 2020-11-11, Last modification date: 2024-01-24)

Primary citation

Kolaric, A.,Germe, T.,Hrast, M.,Stevenson, C.E.M.,Lawson, D.M.,Burton, N.P.,Voros, J.,Maxwell, A.,Minovski, N.,Anderluh, M.
Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.
Nat Commun, 12:150-150, 2021

PubMed Abstract: Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.

PubMed: 33420011
DOI: 10.1038/s41467-020-20405-8

Experimental method

X-RAY DIFFRACTION (2.3 Å)