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Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds

DOI: 10.1038/s41467-020-20405-8 DOI Help

Authors: Anja Kolarič (National Institute of Chemistry; University of Ljubljana) , Thomas Germe (John Innes Centre) , Martina Hrast (University of Ljubljana) , Clare E. M. Stevenson (John Innes Centre) , David M. Lawson (John Innes Centre) , Nicolas P. Burton (Inspiralis Ltd) , Judit Voros (John Innes Centre) , Anthony Maxwell (John Innes Centre) , Nikola Minovski (National Institute of Chemistry, Slovenia) , Marko Anderluh (University of Ljubljana)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 18565

Open Access Open Access

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.

Journal Keywords: Antimicrobials; DNA-binding proteins; Drug discovery and development; X-ray crystallography

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 27/01/2021 10:33

Documents:
s41467-020-20405-8.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)