STRUCTURAL STUDIES OF TRANSCRIPTIONAL REGULATION BY LysR-TYPE TRANSCRIPTIONAL REGULATORS IN BACTERIA

Abstract

LysR-type transcriptional regulators (LTTRs) comprise one of the largest families of transcriptional regulators in bacteria andcontrol gene expression of various types of metabolic, virulence and physiological functions. LTTRs typically form homotetramers and require an inducer molecule(s) to activate the transcription of target genes. The N-terminal region of LTTRs contains a DNAbinding domain (DBD) with the winged helix-turn-helix motif that specifically binds the promoter region of target genes. The C-terminal region of LTTRs is connected to the DBD by a linker helix and forms the regulatory domain (RD) that contains a binding pocket for inducer molecules. Crystal structures of several LTTR family members together with their biochemical analyses have provided a potential mechanism for the initial process of transcriptional activation by LTTRs. First, helix 3 of the winged helix-turn-helix motif in DBD is supposed to distinguish the recognition binding site (RBS) in the promoter region, resulting in complex formation through interactions between two DBDs in the tetrameric LTTR and RBS. Formation of this complex seems to enable interactions between the other two DBDs in the LTTR tetramer and the activation binding site (ABS) in the promoter region.The binding of the tetrameric LTTR to both the RBS and ABS causes the promoter DNA to adopt a bent structure because the four DBDs in the tetrameric LTTR are arranged in a V-shaped manner at the bottom of the LTTR. Interaction of an inducer molecule(s) with the RD seems to cause a quaternary structural change of the LTTR that relaxes the bending angle of the promoter DNA with a concomitant shift of the bound DBDs at the ABS. These events facilitate recruitment of RNA polymerase to its binding site in the promoter region, which overlaps with the ABS for LTTR.

Transcriptional Regulation of the Multiple Resistance Mechanisms in Salmonella—A Review

“…The N-terminal region contains a DNA binding domain (DBD) with an HTH motif specifically binding to the promoter region of target genes. On the other hand, the C-terminus of LysR is connected with DBD via a linker helix, forming a regulator domain (RD) containing a pocket for the binding of inductor molecules [40,158,159]. The characteristics of the LysR family with their assigned role in the virulence of Salmonella are presented in Table 3.…”

Emergence of an Auxin Sensing Domain in Plant-Associated Bacteria

“…Among these families, LysR-type transcriptional regulators (LTTRs) account for ~14% of the total number of TRs and constitute one of the largest families of these regulatory proteins ( 6 ). LTTRs modulate many different biological processes, including metabolism, transport, motility, cell division, antibiotic synthesis, exopolysaccharide production, and stress responses, among others ( 4 , 7 – 9 ), and some bacterial genomes encode over 100 LTTR family members ( 2 , 10 ), suggesting their pivotal role in regulating bacterial physiology and metabolism.…”

“…LTTRs consist of an N-terminal helix-turn-helix DBD connected through a flexible linker to a C-terminal LBD. Although LTTR LBDs are poorly conserved at their amino acid sequence level, they are relatively well conserved in structure ( 7 – 11 )—as exemplified by various three-dimensional (3D) structures available for full-length LTTRs ( 9 , 12 – 15 ) or their individual LBDs ( 6 , 10 , 11 , 16 – 18 ). LTTR-LBDs consist of two α/β subdomains, RD-I and RD-II, that are linked by two antiparallel β-strands to form a cleft between the two subdomains that corresponds to the ligand binding site ( 7 – 10 ).…”

Investigation of salicylidene acylhydrazides derivatives: Molecular Docking, ADMET, and Molecular Dynamic Simulations were used in conjunction towards the design of new Yersinia pseudotuberculosis inhibitors

“…Transcription factor of the LysR type One of the host proteins that could be exploited as a target is RovM. Transcription factor of the LysR type RovM from Yersinia pseudotuberculosis belongs to one of the largest families of prokaryotic transcriptional regulators of genes that code for proteins with a variety of functions, including aromatic compound degradation, amino acid biosynthesis, virulence factor synthesis, CO2fixation, N2-fixation, antibiotic resistance, cell division, quorum sensing, and oxidative stress responses [9]. LysR-type transcriptional regulators typically consist of ~300 amino acids and bind their target promoters as homo-tetramers.…”

“…Transcription factors of the LysR type RovM regulators are a subset of the MarR-like family of transcriptional regulators that regulate several physiological processes in bacterial pathogens, including stress adaption and pathogenicity in response to environmental and host-associated stress [10]. Therefore, due to the essential nature of LysR-type transcription, RovM has been an important drug target for Yersinia pseudotuberculosis inhibitors [9]. Conventional drug findings and the need to develop new and more efficient drugs still represent an unsatisfied challenge [11].…”