Crystal structure of the transcriptional regulator Rv1219c of Mycobacterium tuberculosis

Abstract

The Rv1217c-Rv1218c multidrug efflux system, which belongs to the ATP-binding cassette superfamily, recognizes and actively extrudes a variety of structurally unrelated toxic chemicals and mediates the intrinsic resistance to these antimicrobials in Mycobacterium tuberculosis. The expression of Rv1217c-Rv1218c is controlled by the TetR-like transcriptional regulator Rv1219c, which is encoded by a gene immediately upstream of rv1218c. To elucidate the structural basis of Rv1219c regulation, we have determined the crystal structure of Rv1219c, which reveals a dimeric two-domain molecule with an entirely helical architecture similar to members of the TetR family of transcriptional regulators. The N-terminal domains of the Rv1219c dimer are separated by a large center-to-center distance of 64 Å . The C-terminal domain of each protomer possesses a large cavity. Docking of small compounds to Rv1219c suggests that this large cavity forms a multidrug binding pocket, which can accommodate a variety of structurally unrelated antimicrobial agents. The internal wall of the multidrug binding site is surrounded by seven aromatic residues, indicating that drug binding may be governed by aromatic stacking interactions. In addition, fluorescence polarization reveals that Rv1219c binds drugs in the micromolar range.

Putative TetR family transcriptional regulator Rv1019 ofMycobacterium tuberculosisis an auto-repressor and a negative regulator ofmfd-mazGoperon

“…Many of the TetR family transcriptional regulators are found to be regulating the expression of the gene neighbourhood. For example, transcriptional regulator Rv1219c represses the expression of Rv1217c and Rv1218c involved in multidrug efflux transport system (23, 24). Information provided by the mycobacterium databases shows that two genes, Rv1020 and Rv1021 , are present in the same orientation downstream of Rv1019 .…”

Oleoyl Coenzyme A Regulates Interaction of Transcriptional Regulator RaaS (Rv1219c) with DNA in Mycobacteria

“…During the preparation of this manuscript, a crystal structure of RaaS (Rv1219c) was solved ( 16 ). The structure analysis confirmed our predictions concerning the importance of Arg-140 and Arg-144, but not Tyr-174, in ligand binding.…”

Advancement towards Antibiotic Remediation: Heterostructure and Composite materials

“…The changes result from the spontaneous mutation of a bacterial gene in the chromosome while even a minor change can have an important effect on the target binding. [36] Bacteria have evolved different tactics to achieve this such as:…”

“… Modification of target molecule‐ The prevention of drug binding by changes in the antimicrobial site is a common resistance mechanism. The changes result from the spontaneous mutation of a bacterial gene in the chromosome while even a minor change can have an important effect on the target binding [36] . Bacteria have evolved different tactics to achieve this such as: …”