Targeting a microbiota aminoacyl-tRNA synthetase to block its pathogenic host.

The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases.

Revisiting nucleophilicity: an index for chemical reactivity from a CDFT approach.

Context: Understanding and predicting the nucleophilic reactivity are paramount in elucidating organic chemical reactions and designing new synthetic pathways. In this study, we propose a nucleophilicity index within the framework of Conceptual Density Functional Theory (CDFT). Through rigorous theoretical formulations, we introduce an original quantum reactivity descriptor that captures the nucleophilic propensity of molecules based on their electronic structure and chemical environment.

Expanding horizons in conceptual density functional theory: Novel ensembles and descriptors to decipher reactivity patterns.

Conceptual density functional theory (CDFT) and the quantum reactivity descriptors stemming from it have proven to be valuable tools for understanding the chemical behavior of molecules. This article is presented as being intrinsically of dual character. In a first part, it briefly reviews, in a deliberately didactical way, the main ensembles in CDFT, while the second half presents two additional ensembles, where the chemical hardness acts as a natural variable, and their respective reactivity descriptors.

Insight into the Varying Reactivity of Different Catalysts for CO Cycloaddition into Styrene Oxide: An Experimental and DFT Study.

The cycloaddition of CO into epoxides to form cyclic carbonates is a highly sought-after reaction for its potential to both reduce and use CO, which is a greenhouse gas. In this paper, we present experimental and theoretical studies and a mechanistic approach for three catalytic systems. First, as Lewis base catalysts, imidazole and its derivatives, then as a Lewis acid catalyst, ZnI alone, and after that, the combined system of ZnI and imidazole.

Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase.

Prodrugs have little or no pharmacological activity and are converted to active drugs in the body by enzymes, metabolic reactions, or through human-controlled actions. However, prodrugs promoting their chemical bioconversion without any of these processes have not been reported before. Here, we present an enzyme-independent prodrug activation mechanism by boron-based compounds (benzoxaboroles) targeting leucyl-tRNA synthetase (LeuRS), including an antibiotic that recently has completed phase II clinical trials to cure tuberculosis.

The Automated Crystallography Pipelines at the EMBL HTX Facility in Grenoble.

EMBL Grenoble operates the High Throughput Crystallization Laboratory (HTX Lab), a large-scale user facility offering high throughput crystallography services to users worldwide. The HTX lab has a strong focus in the development of new methods in macromolecular crystallography. Through the combination of a high throughput crystallization platform, the CrystalDirect technology for fully automated crystal mounting and cryocooling and the CRIMS software we have developed fully automated pipelines for macromolecular crystallography that can be remotely operated over the internet.

Di-phosphorylated BAF shows altered structural dynamics and binding to DNA, but interacts with its nuclear envelope partners.

Barrier-to-autointegration factor (BAF), encoded by the BANF1 gene, is an abundant and ubiquitously expressed metazoan protein that has multiple functions during the cell cycle. Through its ability to cross-bridge two double-stranded DNA (dsDNA), it favours chromosome compaction, participates in post-mitotic nuclear envelope reassembly and is essential for the repair of large nuclear ruptures. BAF forms a ternary complex with the nuclear envelope proteins lamin A/C and emerin, and its interaction with lamin A/C is defective in patients with recessive accelerated aging syndromes.

Electrophilicity Indices and Halogen Bonds: Some New Alternatives to the Molecular Electrostatic Potential.

We assess the ability of various atomic and molecular electrophilicity descriptors to predict the strength of halogen bonds. To this aim, several physicochemical quantities rooted within the framework of conceptual density functional theory were derived using second and third order Taylor expansions of the electronic energy, and their correlation to binding energies were compared with those obtained for more usual electronic descriptors. This benchmark was performed for a large and representative database of noncovalent complexes involving fluorine, chlorine, and bromine atoms, and showed that some of these new quantities, in particular the atomic cubic electrophilicity index, exhibited more transferability and broadness of application than did more common descriptors such as the molecular electrostatic potential.

Can molecular and atomic descriptors predict the electrophilicity of Michael acceptors?

In this paper, we assess the ability of various intrinsic molecular and atomic descriptors, grounded in the conceptual density functional theory and the quantum theory of atoms-in-molecules frameworks, to predict the electrophilicity of Michael acceptors, which are fundamental organic reagents involved in the formation of carbon-carbon bonds. To this aim, linear and multilinear regressions between these theoretical properties and the experimental values gathered in Mayr-Patz' scale were performed. The relevance of quantum chemical descriptors are then discussed.

Oxidative C-N fusion of pyridinyl-substituted porphyrins.

The mild (electro)chemical oxidation of pyridin-2-ylthio-meso substituted Ni(ii) porphyrins affords C-N fused cationic and dicationic pyridinium-based derivatives. These porphyrins are fully characterized and the molecular structure of one of them was confirmed by X-ray crystallography. A mechanism for the intramolecular oxidative C-N coupling is proposed based on theoretical calculations and cyclic voltammetry analyses.

Bacterial protease uses distinct thermodynamic signatures for substrate recognition.

Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources.

Three-Dimensional Structure of Full-Length NtrX, an Unusual Member of the NtrC Family of Response Regulators.

Bacteria sense and adapt to environmental changes using two-component systems. These signaling pathways are formed by a histidine kinase that phosphorylates a response regulator (RR), which finally modulates the transcription of target genes. The bacterium Brucella abortus codes for a two-component system formed by the histidine kinase NtrY and the RR NtrX that participates in sensing low oxygen tension and generating an adaptive response.

Automated harvesting and processing of protein crystals through laser photoablation.

Currently, macromolecular crystallography projects often require the use of highly automated facilities for crystallization and X-ray data collection. However, crystal harvesting and processing largely depend on manual operations. Here, a series of new methods are presented based on the use of a low X-ray-background film as a crystallization support and a photoablation laser that enable the automation of major operations required for the preparation of crystals for X-ray diffraction experiments.

Quantitative and predictive model of kinetic regulation by E. coli TPP riboswitches.

Riboswitches are non-coding elements upstream or downstream of mRNAs that, upon binding of a specific ligand, regulate transcription and/or translation initiation in bacteria, or alternative splicing in plants and fungi. We have studied thiamine pyrophosphate (TPP) riboswitches regulating translation of thiM operon and transcription and translation of thiC operon in E. coli, and that of THIC in the plant A.

Structure-guided discovery of a novel aminoglycoside conjugate targeting HIV-1 RNA viral genome.

The dimerization initiation site (DIS) of the HIV-1 genomic RNA is a conserved stem-loop that promotes viral genome dimerization by forming a loop-loop complex. The DIS constitutes a potentially interesting target because it is crucial for several key steps of the viral replication. In this work we describe the synthesis of a rationally designed aminoglycoside conjugate that binds the HIV-1 DIS viral RNA with high specificity, as shown by an extensive in vitro binding characterization.

kinITC: a new method for obtaining joint thermodynamic and kinetic data by isothermal titration calorimetry.

Isothermal titration calorimetry (ITC) is the method of choice for obtaining thermodynamic data on a great variety of systems. Here we show that modern ITC apparatus and new processing methods allow researchers to obtain a complete kinetic description of systems more diverse than previously thought, ranging from simple ligand binding to complex RNA folding. We illustrate these new features with a simple case (HIV-1 reverse transcriptase/inhibitor interaction) and with the more complex case of the folding of a riboswitch triggered by the binding of its ligand.