5CTW

Crystal structure of the ATP binding domain of S. aureus GyrB complexed with a fragment

Summary for 5CTW

• Entry DOI: 10.2210/pdb5ctw/pdb
• Related: 5CPH 5CTU 5CTX 5CTY
• Descriptor: DNA gyrase subunit B, 2-(butanoylamino)thiophene-3-carboxamide, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: dna gyrase, gyrb, fragment-based screening, structure-based design, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Staphylococcus aureus
• Cellular location: Cytoplasm : P0A0K8
• Total number of polymer chains: 2
• Total formula weight: 48998.13

Authors

Andersen, O.A.,Barker, J.,Hadfield, A.T.,Cheng, R.K.,Kahmann, J.,Felicetti, B.,Wood, M.,Scheich, C.,Mesleh, M.,Cross, J.B.,Zhang, J.,Yang, Q.,Lippa, B.,Ryan, M.D. (deposition date: 2015-07-24, release date: 2016-02-03, Last modification date: 2023-09-27)

Primary citation

Mesleh, M.F.,Cross, J.B.,Zhang, J.,Kahmann, J.,Andersen, O.A.,Barker, J.,Cheng, R.K.,Felicetti, B.,Wood, M.,Hadfield, A.T.,Scheich, C.,Moy, T.I.,Yang, Q.,Shotwell, J.,Nguyen, K.,Lippa, B.,Dolle, R.,Ryan, M.D.
Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.
Bioorg.Med.Chem.Lett., 26:1314-1318, 2016

PubMed Abstract: Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 μM inhibitor is described herein.

PubMed: 26786695
DOI: 10.1016/j.bmcl.2016.01.009

Experimental method

X-RAY DIFFRACTION (1.48 Å)