4HXW

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.

Summary for 4HXW

• Entry DOI: 10.2210/pdb4hxw/pdb
• Related: 4GEE 4GFN 4GGL 4HXZ 4HY1 4HYM 4HYP 4HZ0 4HZ5
• Descriptor: DNA gyrase subunit B, (3R)-1-[5-chloro-6-ethyl-2-(pyrido[2,3-b]pyrazin-7-ylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-amine, TERTIARY-BUTYL ALCOHOL, ... (4 entities in total)
• Functional Keywords: atp-binding, nucleotide-binding, topoisomerase, atp-binding domain, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Enterococcus faecalis
• Cellular location: Cytoplasm (By similarity): Q839Z1
• Total number of polymer chains: 1
• Total formula weight: 24336.66

Authors

Bensen, D.C.,Trzoss, M.,Tari, L.W. (deposition date: 2012-11-12, release date: 2013-02-13, Last modification date: 2024-02-28)

Primary citation

Tari, L.W.,Trzoss, M.,Bensen, D.C.,Li, X.,Chen, Z.,Lam, T.,Zhang, J.,Creighton, C.J.,Cunningham, M.L.,Kwan, B.,Stidham, M.,Shaw, K.J.,Lightstone, F.C.,Wong, S.E.,Nguyen, T.B.,Nix, J.,Finn, J.
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, 2013

PubMed 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.

PubMed: 23352267
DOI: 10.1016/j.bmcl.2012.11.032

Experimental method

X-RAY DIFFRACTION (1.69 Å)