Comprehensive kinetic characterization and inhibitor study of Ribonuclease E, a key enzyme of RNA metabolism from Mycobacterium smegmatis.

Ribonuclease E (RNase E) in Mycobacterium species is an essential gene that plays a crucial role in RNA metabolism. This is the first detailed kinetic characterization of recombinant RNase E and its deletion mutants, along with virtual high-throughput ligand screening (vHTS) and in vitro inhibitor studies from any Mycobacterium species. Recombinant wild-type RNase E and its deletion mutants of Mycobacterium smegmatis (M.

RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates.

Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues.

Structural Insight Into the Conversion of DhNik1, A Hybrid Histidine Kinase From Debaryomyces hansenii to a Cytotoxic Phosphatase Conformation for Novel Antifungal Agent.

Group III hybrid histidine kinase (HHK3) is one of the most interesting signalling molecules and a novel drug target in fungi. HHK3 is converted into a cytotoxic phosphatase form in vivo by the action of a widely used agricultural fungicide indicating that HHK3 also exhibits dual functionality by acting as kinases and phosphatases towards their substrates like many bacterial sensor histidine kinases. However, this cytotoxic form of HHK3 remained elusive for further scientific exploitation.

Disordered Regions of Condensate-promoting Proteins Have Distinct Molecular Signatures Associated with Cellular Function.

Disordered regions of proteins play crucial roles in cellular functions through diverse mechanisms. Some disordered regions function by promoting the formation of biomolecular condensates through dynamic multivalent interactions. While many have assumed that interactions among these condensate-promoting disordered regions are non-specific, recent studies have shown that distinct sequence compositions and patterning lead to specific condensate compositions associated with cellular function.

The Cell Division Activator Protein StCAP Impacts Pathogenesis by Influencing Critical Molecular Events.

Conserved molecular signatures in multidrug-resistant can serve as novel therapeutic targets for mitigation of infection. In this regard, we present the cell division activator protein (StCAP) as a conserved target across variants. From and fluorimetric assessments, we found that StCAP is a DNA-binding protein.

Spike Protein Mutation-Induced Changes in the Kinetic and Thermodynamic Behavior of Its Receptor Binding Domains Explain Their Higher Propensity to Attain Open States in SARS-CoV-2 Variants of Concern.

Spike (S) protein opening in SARS-CoV-2 controls the accessibility of its receptor binding domains (RBDs) to host receptors and immune recognition. Along the evolution of SARS-CoV-2 to its variants of concern (VOC)-alpha, beta, gamma, delta, and omicron-their S proteins showed a higher propensity to attain open states. Deciphering how mutations in S protein can shape its conformational dynamics will contribute to the understanding of viral host tropism.

Evolutionarily conserved heat shock protein, HtpX, as an adjunct target against antibiotic-resistant Neisseria gonorrhoeae.

The emergence of multiple drug resistance and extreme drug resistance pathogens necessitates the continuous evaluation of the pathogenic genome to identify conserved molecular targets and their respective inhibitors. In this study, we mapped the global mutational landscape of Neisseria gonorrhoeae (an intracellular pathogen notoriously known to cause the sexually transmitted disease gonorrhoea). We identified highly variable amino acid positions in the antibiotic target genes like the penA, ponA, 23s rRNA, rpoB, gyrA, parC, mtrR and porB.

Deoxyelephantopin-a novel PPARγ agonist regresses pressure overload-induced cardiac fibrosis via IL-6/STAT-3 pathway in crosstalk with PKCδ.

Pathological cardiac hypertrophy is associated with ventricular fibrosis leading to heart failure. The use of thiazolidinediones as Peroxisome Proliferator-Activated Receptor-gamma (PPARγ)-modulating anti-hypertrophic therapeutics has been restricted due to major side-effects. The present study aims to evaluate the anti-fibrotic potential of a novel PPARγ agonist, deoxyelephantopin (DEP) in cardiac hypertrophy.

Polypharmacological repurposing approach identifies approved drugs as potential inhibitors of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative pathogen of tuberculosis (TB) remains the leading cause of death from single infectious agent. Furthermore, its evolution to multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains necessitate de novo identification of drug-targets/candidates or to repurpose existing drugs against known targets through drug repurposing.

Energetics of Spike Protein Opening of SARS-CoV-1 and SARS-CoV-2 and Its Variants of Concern: Implications in Host Receptor Scanning and Transmission.

The receptor binding domain(s) (RBD) of spike (S) proteins of SARS-CoV-1 and SARS-CoV-2 (severe acute respiratory syndrome coronavirus) undergoes closed to open transition to engage with host ACE2 receptors. In this study, using multi atomistic (equilibrium) and targeted (non-equilibrium) molecular dynamics simulations, we have compared energetics of RBD opening pathways in full-length (modeled from cryo-EM structures) S proteins of SARS-CoV-1 and SARS-CoV-2. Our data indicate that amino acid variations at the RBD interaction interface can culminate into distinct free energy landscapes of RBD opening in these S proteins.

In-silico design of an immunoinformatics based multi-epitope vaccine against Leishmania donovani.

Background: Visceral Leishmaniasis (VL) is a fatal vector-borne parasitic disorder occurring mainly in tropical and subtropical regions. VL falls under the category of neglected tropical diseases with growing drug resistance and lacking a licensed vaccine. Conventional vaccine synthesis techniques are often very laborious and challenging.

Structure and Sequence Based Analysis of Pullulanases: Understanding Dual Catalytic Mechanism.

Background: Starch processing requires a combination of enzymes with other chemical and physical processes, which increases cost and time. Enzymes used in these processes have a characteristic (α/β)8 barrel domain architecture, although, show variable activity. Pullulanase type 1 and isoamylase act on α-1-6 linkage, amylase on α-1-4 linkage whereas pullulanase type 2 acts on both α-1-6, and α-1-4 linkages of starch.