PDBsum entry 4zvi

Isomerase

PDB id: 4zvi

Contents

Protein chain

357 a.a.

Ligands

4S4

Metals

IOD ×2

Waters ×76

PDB id:

4zvi

Name:

Isomerase

Title:

Gyrase b in complex with 4,5-dibromopyrrolamide-based inhibitor

Structure:

DNA gyrase subunit b. Chain: a. Fragment: n-terminal domain, residues 16-392. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Gene: gyrb, z5190, ecs4634. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.20Å R-factor: 0.228 R-free: 0.282

Authors:

N.Zidar,H.Macut,T.Tomasic,M.Brvar,S.Montalvao,P.Tammela,T.Solmajer, L.Peterlin Masic,J.Ilas,D.Kikelj

Key ref:

N.Zidar et al. (2015). N-Phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATP Competitive DNA Gyrase B Inhibitors: Design, Synthesis, and Evaluation. J Med Chem, 58, 6179-6194. PubMed id: 26126187 DOI: 10.1021/acs.jmedchem.5b00775

Date:

18-May-15 Release date: 15-Jul-15

Protein chain

P0AES7  (GYRB_ECO57) -  DNA gyrase subunit B from Escherichia coli O157:H7

Seq: 804 a.a.

Struc: 357 a.a.

Enzyme reactions

• Enzyme class: E.C.5.6.2.2 - Dna topoisomerase (ATP-hydrolyzing).

DOI no: 10.1021/acs.jmedchem.5b00775

J Med Chem 58:6179-6194 (2015)

PubMed id: 26126187

N-Phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATP Competitive DNA Gyrase B Inhibitors: Design, Synthesis, and Evaluation.

N.Zidar, H.Macut, T.Tomašič, M.Brvar, S.Montalvão, P.Tammela, T.Solmajer, L.Peterlin Mašič, J.Ilaš, D.Kikelj.

ABSTRACT

Bacterial DNA gyrase is a well-known and validated target in the design of antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase B (GyrB), have so far not reached clinical use. In the present study, three different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values of compounds on DNA gyrase from Escherichia coli were in the low micromolar range, with the best compound, (4-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzoyl)glycine (18a), displaying an IC50 of 450 nM. For this compound, a high-resolution crystal structure in complex with E. coli DNA gyrase B was obtained, revealing details of its binding mode within the active site. The binding affinities of three compounds with GyrB were additionally evaluated by surface plasmon resonance, and the results were in good agreement with the determined enzymatic activities. For the most promising compounds, the inhibitory activities against DNA gyrase from Staphylococcus aureus and topoisomerases IV from E. coli and S. aureus were determined. Antibacterial activities of the most potent compounds of each series were evaluated against two Gram-positive and two Gram-negative bacterial strains. The results obtained in this study provide valuable information on the binding mode and structure-activity relationship of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as promising classes of ATP competitive GyrB inhibitors.