7z9c

E.coli gyrase holocomplex with 217 bp DNA and albicidinE.coli gyrase holocomplex with 217 bp DNA and albicidin

Structural highlights

7z9c is a 8 chain structure with sequence from Escherichia coli str. K-12 substr. MG1655 and Escherichia phage Mu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.06Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GYRA_ECOLI DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.^[1] ^[2] ^[3]

Publication Abstract from PubMed

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 A resolution cryoelectron microscopy structure of a ternary complex between Escherichia coli 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 E. coli 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.

Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin.,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 JB, Mainz A, Heddle JG, Sussmuth RD, Ghilarov D Nat Catal. 2023;6(1):52-67. doi: 10.1038/s41929-022-00904-1. Epub 2023 Jan 23. PMID:36741192^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hockings SC, Maxwell A. Identification of four GyrA residues involved in the DNA breakage-reunion reaction of DNA gyrase. J Mol Biol. 2002 Apr 26;318(2):351-9. PMID:12051842 doi:http://dx.doi.org/10.1016/S0022-2836(02)00048-7
↑ Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:http://dx.doi.org/10.1021/bi800480j
↑ Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Le TB, Clarke TA, McKay AR, Fiedler HP, Buttner MJ, Lawson DM, Maxwell A. A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science. 2009 Dec 4;326(5958):1415-8. PMID:19965760 doi:326/5958/1415
↑ Michalczyk E, Hommernick K, Behroz I, Kulike M, Pakosz-Stępień Z, Mazurek L, Seidel M, Kunert M, Santos K, von Moeller H, Loll B, Weston JB, Mainz A, Heddle JG, Süssmuth RD, Ghilarov D. Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin. Nat Catal. 2023;6(1):52-67. PMID:36741192 doi:10.1038/s41929-022-00904-1

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OCA

[1] Hockings SC, Maxwell A. Identification of four GyrA residues involved in the DNA breakage-reunion reaction of DNA gyrase. J Mol Biol. 2002 Apr 26;318(2):351-9. PMID:12051842 doi:http://dx.doi.org/10.1016/S0022-2836(02)00048-7

[2] Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:http://dx.doi.org/10.1021/bi800480j

[3] Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Le TB, Clarke TA, McKay AR, Fiedler HP, Buttner MJ, Lawson DM, Maxwell A. A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science. 2009 Dec 4;326(5958):1415-8. PMID:19965760 doi:326/5958/1415

[4] Michalczyk E, Hommernick K, Behroz I, Kulike M, Pakosz-Stępień Z, Mazurek L, Seidel M, Kunert M, Santos K, von Moeller H, Loll B, Weston JB, Mainz A, Heddle JG, Süssmuth RD, Ghilarov D. Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin. Nat Catal. 2023;6(1):52-67. PMID:36741192 doi:10.1038/s41929-022-00904-1

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