7Z9C

E.coli gyrase holocomplex with 217 bp DNA and albicidin

Summary for 7Z9C

• Entry DOI: 10.2210/pdb7z9c/pdb
• EMDB information: 14570
• Descriptor: DNA gyrase subunit A, DNA gyrase subunit B, DNA (5'-D(P*AP*AP*AP*TP*CP*TP*GP*TP*GP*CP*GP*GP*GP*T)-3'), ... (9 entities in total)
• Functional Keywords: type ii topoisomerase, antibiotic, albicidin, dna gyrase, isomerase
• Biological source: Escherichia coli str. K-12 substr. MG1655; More
• Total number of polymer chains: 8
• Total formula weight: 397973.30

Authors

Ghilarov, D.,Heddle, J.G.H.,Suessmuth, R. (deposition date: 2022-03-21, release date: 2023-02-15, Last modification date: 2024-11-13)

Primary citation

Michalczyk, E.,Hommernick, K.,Behroz, I.,Kulike, M.,Pakosz-Stepien, Z.,Mazurek, L.,Seidel, M.,Kunert, M.,Santos, K.,von Moeller, H.,Loll, B.,Weston, J.B.,Mainz, A.,Heddle, J.G.,Sussmuth, R.D.,Ghilarov, D.
Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin.
Nat Catal, 6:52-67, 2023

PubMed Abstract: The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is poorly understood. We determined a 2.6 Å resolution cryoelectron microscopy structure of a ternary complex between topoisomerase DNA gyrase, a 217 bp double-stranded DNA fragment and albicidin. Albicidin employs a dual binding mechanism where one end of the molecule obstructs the crucial gyrase dimer interface, while the other intercalates between the fragments of cleaved DNA substrate. Thus, albicidin efficiently locks DNA gyrase, preventing it from religating DNA and completing its catalytic cycle. Two additional structures of this trapped state were determined using synthetic albicidin analogues that demonstrate improved solubility, and activity against a range of gyrase variants and topoisomerase IV. The extraordinary promiscuity of the DNA-intercalating region of albicidins and their excellent performance against fluoroquinolone-resistant bacteria holds great promise for the development of last-resort antibiotics.

PubMed: 36741192
DOI: 10.1038/s41929-022-00904-1

Experimental method

ELECTRON MICROSCOPY (3.06 Å)