PDBsum entry 4hyp

Isomerase/isomerase inhibitor

PDB id: 4hyp

Contents

Protein chains

194 a.a.

Ligands

1A1 ×4

Metals

_MG ×4

Waters ×375

PDB id:

4hyp

Name:

Isomerase/isomerase inhibitor

Title:

Pyrrolopyrimidine inhibitors of DNA gyrase b and topoisomerase iv, part i: structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.

Structure:

DNA gyrase subunit b. Chain: a, b, c, d. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: acrb, b3699, gyrb, himb, hisu, jw5625, nalc. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.60Å R-factor: 0.200 R-free: 0.294

Authors:

D.C.Bensen,C.J.Creighton,L.W.Tari

Key ref:

L.W.Tari et al. (2013). Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. Bioorg Med Chem Lett, 23, 1529-1536. PubMed id: 23352267

Date:

13-Nov-12 Release date: 13-Feb-13

Protein chains

P0AES6  (GYRB_ECOLI) -  DNA gyrase subunit B from Escherichia coli (strain K12)

Seq: 804 a.a.

Struc: 194 a.a.

Enzyme reactions

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

Bioorg Med Chem Lett 23:1529-1536 (2013)

PubMed id: 23352267

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.

L.W.Tari, M.Trzoss, D.C.Bensen, X.Li, Z.Chen, T.Lam, J.Zhang, C.J.Creighton, M.L.Cunningham, B.Kwan, M.Stidham, K.J.Shaw, F.C.Lightstone, S.E.Wong, T.B.Nguyen, J.Nix, J.Finn.

ABSTRACT

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.