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Publication Abstract from PubMed

Tetracycline Repressors (TetRs) modulate multi-drug efflux pathways in several pathogenic bacteria. In Streptomyces, they additionally regulate secondary metabolic pathways like antibiotic production. For instance, in the antibiotic producer Streptomyces fradiae, a layered network of TetRs regulate the levels of commercially important antibiotic tylosin, with TylP occupying the top of this cascading network. TetRs exist in two functional states; the DNA-bound and the ligand-bound form, which are allosterically regulated. Here, to develop deeper insights into the factors that govern allostery, the crystal structure of TylP was solved to a resolution of 2.3 A. The structure reveals that TylP possesses several unique features; notably, it harbors an unique C-terminal helix-loop extension that spans the entire length of the structure. This anchor connects the DNA binding domain (DBD) with the ligand binding domain (LBD) via a mix of positively charged and hydrogen-bonding interactions. Supporting EMSA studies with a series of DeltaC truncated versions show that a systematic deletion of this region results in complete loss of DNA binding. The structure additionally reveals that TylP is markedly different in the orientation of its DBD, LBD architecture and the dimeric geometry, from its hypothesized Streptomyces homologue CprB, which is a gamma- butyrolactone regulator. Rather, TylP is closer in structural design to macrolide binding TetRs, found in pathogens. Supporting MD studies suggest that TylP binds a macrolide intermediate in the tylosin pathway. Collectively, the structure along with corroborating biochemical studies provides insights into the novel mode of regulation of TetRs in antibiotic producing organisms.

Functional Insights into the Mode of DNA and Ligand Binding of the TetR Family Regulator TylP from Streptomyces fradiae.,Ray S, Maitra A, Biswas A, Panjikar S, Mondal J, Anand R J Biol Chem. 2017 Jul 24. pii: jbc.M117.788000. doi: 10.1074/jbc.M117.788000. PMID:28739805^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.