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The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X‐ray crystallography.
Author(s) -
Lewis R. J.,
Singh O. M.,
Smith C. V.,
Skarzynski T.,
Maxwell A.,
Wonacott A. J.,
Wigley D. B.
Publication year - 1996
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1996.tb00483.x
Subject(s) - dna gyrase , novobiocin , biology , dna , topoisomerase , escherichia coli , dna supercoil , biochemistry , binding site , ligand (biochemistry) , stereochemistry , dna replication , gene , chemistry , antibiotics , receptor
This study describes the first crystal structures of a complex between a DNA topoisomerase and a drug. We present the structures of a 24 kDa N‐terminal fragment of the Escherichia coli DNA gyrase B protein in complexes with two different inhibitors of the ATPase activity of DNA gyrase, namely the coumarin antibiotic, novobiocin, and GR1X, a member of the cyclothialidine family. These structures are compared with the crystal structure of the complex with an ATP analogue, adenylyl‐beta‐gamma‐imidodiphosphate (ADPNP). The likely mechanism, by which mutant gyrase B proteins become resistant to inhibition by novobiocin are discussed in light of these comparisons. The three ligands are quite dissimilar in chemical structure and bind to the protein in very different ways, but their binding is competitive because of a small degree of overlap of their binding sites. These crystal structures consequently describe a chemically well characterized ligand binding surface and provide useful information to assist in the design of novel ligands.