Molecular mechanisms underlying allosteric behavior of Escherichia coli DgoR, a GntR/FadR family transcriptional regulator.

GntR/FadR family featuring an N-terminal winged helix-turn-helix DNA-binding domain and a C-terminal α-helical effector-binding and oligomerization domain constitutes one of the largest families of transcriptional regulators. Several GntR/FadR regulators govern the metabolism of sugar acids, carbon sources implicated in bacterial-host interactions. Although effectors are known for a few sugar acid regulators, the unavailability of relevant structures has left their allosteric mechanism unexplored.

Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.

The potency of frontline antimalarial drug artemisinin (ART) derivatives is triggered by heme-induced cleavage of the endoperoxide bond to form reactive heme-ART alkoxy radicals and covalent heme-ART adducts, which are highly toxic to the parasite. ART-resistant (ART-R) parasites with mutations in the Plasmodium falciparum Kelch-containing protein Kelch13 (PfKekch13) exhibit impaired hemoglobin uptake, reduced yield of hemoglobin-derived heme, and thus decreased ART activation. However, any direct involvement of PfKelch13 in heme-mediated ART activation has not been reported.

Factor defining the effects of tetraalkylammonium chloride on stability, folding, and dynamics of horse cytochrome c.

This article describes the molecular mechanism by which tetraalkylammonium chloride ([RN]Cl: R- = methyl (Me), ethyl (Et), propyl (Pr),butyl (Bu)) modulates the stability, folding, and dynamics of cytochrome c (Cyt c). Analysis of [RN]Cl effects on thermal/chemical denaturations, millisecond refolding/unfolding kinetics, and slow CO-association kinetics of Cyt c without and with denaturant providing some significant results: (i) [RN]Cl decreasing the unfolding free energy estimated by thermodynamic and kinetic analysis of thermal/chemical denaturation curves and kinetic chevrons (Log k-[GdmCl]) of Cyt c, respectively (ii) hydrophobicity of R-group of [RN]Cl, preferential inclusion of [RN]Cl at the protein surface, and destabilizing enthalpic attractive interactions of [MeN]Cl and steric entropic interactions of [EtN]Cl,[PrN]Cl and [BuN]Cl with protein contribute to [RN]Cl-induced decrease thermodynamic stability of Cyt c (iii) [RN]Cl exhibits an additive effect with denaturant to decrease thermodynamic stability and refolding rates of Cyt c (iv) low concentrations of [RN]Cl (≤ 0.5 M) constrain the motional dynamics while the higher concentrations (>0.

Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs.

The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins.

Biochemical and structural characterization reveals Rv3400 codes for β-phosphoglucomutase in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) adapt to various host environments and utilize a variety of sugars and lipids as carbon sources. Among these sugars, maltose and trehalose, also play crucial role in bacterial physiology and virulence. However, some key enzymes involved in trehalose and maltose metabolism in Mtb are not yet known.

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases.

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy.

A sucrose non-fermenting-1-related protein kinase 1 gene from wheat, TaSnRK1α regulates starch biosynthesis by modulating AGPase activity.

Major portion of wheat grain consist of carbohydrate, mainly starch. The proportion of amylose and amylopectin in starch greatly influence the end product quality. Advancement in understanding starch biosynthesis pathway and modulating key genes has enabled the genetic modification of crops resulting in enhanced starch quality.

The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival.

Mycobacterium tuberculosis has evolved several mechanisms to counter host defense arsenals for its proliferation. Here we report that M. tuberculosis employs a multi-pronged approach to modify host epigenetic machinery for its survival.

A Reappraisal of the Antiviral Properties of and Immune Regulation through Dietary Phytochemicals.

In the present era of the COVID-19 pandemic, viral infections remain a major cause of morbidity and mortality worldwide. In this day and age, viral infections are rampant and spreading rapidly. Among the most aggressive viral infections are ebola, AIDS (acquired immunodeficiency syndrome), influenza, and SARS (severe acute respiratory syndrome).

Single-molecule analysis of osmolyte-mediated nanomechanical unfolding behavior of a protein domain.

The small organic molecules, known as osmolytes being ubiquitously present in different cell types, affect protein folding, stability and aggregation. However, it is unknown how the osmolytes affect the nanomechanical unfolding behavior of protein domain. Here, we show the osmolyte-dependent mechanical unfolding properties of protein titin immunoglobulin-27 (I27) domain using an atomic force microscopy (AFM)-based single-molecule force spectroscopy.

Mycobacterium tuberculosis H37Rv enolase (Rv1023)- expression, characterization and effect of host dependent modifications on protein functionality.

Mycobacterium tuberculosis enolase is an essential glycolytic enzyme that catalyzes the conversion of 2, phosphoglycerate (PGA) to phosphoenol pyruvate (PEP). It is also a crucial link between glycolysis and the tricarboxylic acid (TCA) pathway. The depletion of PEP has recently been associated with the emergence of non-replicating drug resistant bacteria.

TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3.

The outcome of the disease visceral leishmaniasis (VL), caused by Leishmania donovani (LD), largely relies on the relative dominance of host-protective type-1 T helper (Th1) cell response versus disease-promoting type-2 T helper (Th2) cell response. The Th1 and Th2 responses, in turn, are believed to be elicited by type-1 conventional dendritic cells (cDC1) and type-2 conventional DCs (cDC2), respectively. However, it is still unknown which DC subtype (cDC1 or cDC2) predominates during chronic LD infection and the molecular mechanism governing such occurrence.

Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β.

To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood.

Characterization of the enzymatic and multifunctional properties of Acinetobacter baumannii erythrose-4-phosphate dehydrogenase (E4PDH).

Infections due to Acinetobacter baumannii (A. baumannii) are rapidly increasing worldwide and consequently therapeutic options for treatment are limited. The emergence of multi drug resistant (MDR) strains has rendered available antibiotics ineffective, necessitating the urgent discovery of new drugs and drug targets.

Biocide-Resistant ST540 Co-Harboring ESBL, Confers QnrS-Dependent Plasmid-Mediated Quinolone Resistance.

Emerging sequence types of pathogenic bacteria have a dual ability to acquire resistance islands/determinants, and remain renitent towards disinfection practices; therefore, they are considered "critical risk factors" that contribute significantly to the global problem of antimicrobial resistance. Multidrug-resistant was isolated, its genome sequenced, and its susceptibilities characterized, in order to understand the genetic basis of its antimicrobial resistance.The draft genome sequencing of ECU32, was performed with Illumina NextSeq 500, and annotated using a RAST server.

A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers.

Parkinson's disease is a neurodegenerative movement disorder associated with the intracellular aggregation of α-synuclein (α-syn). Cytotoxicity is mainly associated with the oligomeric species (αSOs) formed at early stages in α-syn aggregation. Consequently, there is an intense focus on the discovery of novel inhibitors such as peptides to inhibit oligomer formation and toxicity.

Ydj1 interaction at nucleotide-binding-domain of yeast Ssa1 impacts Hsp90 collaboration and client maturation.

Hsp90 constitutes one of the major chaperone machinery in the cell. The Hsp70 assists Hsp90 in its client maturation though the underlying basis of the Hsp70 role remains to be explored. In the present study, using S.

Disruption of MenT2 toxin impairs the growth of in guinea pigs.

Toxin-antitoxin (TA) systems are abundantly present in the genomes of various bacterial pathogens. TA systems have been implicated in either plasmid maintenance or protection against phage infection, stress adaptation or disease pathogenesis. The genome of encodes for more than 90 TA systems and 4 of these belong to the type IV subfamily (MenAT family).

Substitution of carbonate by non-physiological synergistic anion modulates the stability and iron release kinetics of serum transferrin.

Serum transferrin (sTf) is a bi-lobal protein. Each lobe of sTf binds one Fe ion in the presence of a synergistic anion. Physiologically, carbonate is the main synergistic anion but other anions such as oxalate, malonate, glycolate, maleate, glycine, etc.

Analysis of the effect of 1-Allyl-3-Methylimidazolium chloride on thermodynamic stability, folding kinetics, and motional dynamics of horse cytochrome c.

1-allyl-3-methylimidazolium chloride (AMIMCl) acts as a potential green solvent for proteins. The present work provides a possible pathway by which the structural, kinetic, thermodynamic, and folding properties of horse cytochrome c (cyt c) are affected in green aqueous-AMIMCl systems. Analysis of the effect of AMIMCl on thermodynamic stability, refolding/unfolding kinetics, and motional dynamics of cyt c provided important information, (i) AMIMCl decreases the thermodynamic stability of reduced cyt c and also strengthens the guanidinium chloride (GdmCl)-mediated decrease in thermodynamic stability of protein, (ii) AMIMCl reduces the thermal-fluctuation of Met80-containing omega-loop of natively-folded compact state of carbonmonoxycytochrome c (MCO-state) due to polyfunctional interactions between the AMIM and different groups of protein, (iii) AMIMCl shifts the kinetic chevron plot, ln k[GdmCl] to the lower concentration of GdmCl, (iv) AMIMCl shifts the refolding and unfolding limps to vertically downwards and upwards, respectively, and (v) AMIMCl reducing the unfolding free energy estimated by both thermodynamic and kinetic analysis.

Identification of small molecules targeting homoserine acetyl transferase from Mycobacterium tuberculosis and Staphylococcus aureus.

There is an urgent need to validate new drug targets and identify small molecules that possess activity against both drug-resistant and drug-sensitive bacteria. The enzymes belonging to amino acid biosynthesis have been shown to be essential for growth in vitro, in vivo and have not been exploited much for the development of anti-tubercular agents. Here, we have identified small molecule inhibitors targeting homoserine acetyl transferase (HSAT, MetX, Rv3341) from M.

Leishmania donovani Impedes Antileishmanial Immunity by Suppressing Dendritic Cells via the TIM-3 Receptor.

An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L.

Deep Population Genomics Reveals Systematic and Parallel Evolution at a Lipopolysaccharide Biosynthetic Locus in Pathogens That Infect Rice and Sugarcane.

The advent of high-throughput sequencing and population genomics has enabled researchers to investigate selection pressure at hypervariable genomic loci encoding pathogen-associated molecular pattern (PAMP) molecules like lipopolysaccharide (LPS). Xanthomonas is a model and a major group of phytopathogenic bacteria that infect hosts in tissue-specific manner. Our in-depth population-based genomic investigation revealed the emergence of major lineages in two Xanthomonas pathogens that infect xylem of rice and sugarcane is associated with the acquisition and later large-scale replacement by distinct type of LPS cassettes.

Plasmodium falciparum Kelch13 and its artemisinin-resistant mutants assemble as hexamers in solution: a SAXS data-driven modelling study.

The artemisinin-resistant mutations in Plasmodium falciparum (PfKelch13) identified worldwide are mostly confined to the Broad-complex, tramtrack and bric-à-brac/poxvirus and zinc-finger (BTB/POZ) and Kelch-repeat propeller (KRP) domains. To date, only two crystal structures of the BTB/POZ-KRP domains as tight dimers are available, which limits structure-based predictions and interpretation of its role(s) in inducing clinical artemisinin resistance. Our solution Small-Angle X-ray Scattering (SAXS) data analysis and shape restoration brought forth that: (a) PfKelch13 forms a stable hexamer in P6 symmetry, (b) interactions of the N-termini drive the hexameric assembly, and (c) the six KRP domains project independently in space, forming a cauldron-like architecture.