Communications Chemistry最新文献

DNAzymes conventionally require dissolved metal ions for catalytic functions. Herein, we report that metal surfaces directly activate a self-cleaving DNAzyme (PL) at solid-liquid interfaces. PL exhibits activities on copper, vanadium and tantalum surfaces, within a minimal reaction system comprising only the metal surface, PL and double-distilled water. This interfacial activation is highly material-specific, showing complete absence of activity on plastics, glass or wood etc. Mechanistic studies reveal that dissolved oxygen could react with metal surfaces to generate superoxide anions, which serve as triggers for DNA-cleavage. The reaction shows modulatable characteristics, with inhibition by ethylenediaminetetraacetic acid, catalase, nitroblue tetrazolium and cytochrome c, versus enhancement by vitamin C, glutathione and catechol. Furthermore, metal surface-mediated activation was also observed in F-8, Ag10c and I-R3 DNAzymes, indicating that this phenomenon is not an isolated occurrence. This work establishes macroscopic metals as DNAzyme's cofactors, extending DNAzyme catalysis beyond conventional homogeneous systems to heterogeneous interfacial environments.

The TEAD transcription factors (TEAD1-4) are critical effectors of the Hippo pathway, forming active nuclear complexes with transcriptional co-activators YAP/TAZ to regulate cell growth/apoptosis pathways and control fundamental processes such as organ size. Frequent dysregulation of the Hippo pathway in cancer and the presence of druggable binding sites on TEADs make them attractive targets for development of small molecule inhibitors and degraders. Here, we identify and mechanistically characterize three unique series of bifunctional degraders that target TEAD1 via a lipid pocket and recruit different members of the Inhibitor of Apoptosis proteins (IAPs) family to effect degradation of TEAD1. We provide a detailed toolkit for structural, biophysical and cellular profiling, including the development of a cellular target engagement assay for the lipid pocket of TEAD1 and an IAP/TEAD1 ternary complex formation assay. Our study therefore provides essential resources for detailed characterization of IAP-recruiting degraders and important tools and learnings for bifunctional degraders targeted to the lipid pocket of TEADs.

Deoxyhypusine synthase (DHS) catalyzes the rate-limiting step of hypusination, a unique post-translational modification of eukaryotic translation factor 5 A (eIF5A). While DHS activity plays a critical role in both normal cellular processes and disease development, the lack of specific molecular tools has hindered detailed studies of this enzyme and the hypusination pathway in general. Existing inhibitors, such as polyamine analogs, suffer from limited specificity and versatility. In this study, we utilized crystallographic fragment screening (CFS) to identify potential DHS inhibitors and explore novel applications of this approach. With an unprecedented hit rate of 39%, we identified fragment clusters binding at key sites, including the active site entrance, the tetramer interface, the regulatory ball-and-chain motif, and potentially allosteric regions on the enzyme's surface. Notably, we discovered a covalent modifier that targets the catalytic lysine residue in an oxidoreductase reaction-specific manner, as well as fragments that induce significant structural rearrangements of crucial regulatory elements. Our findings establish a framework for extending CFS beyond traditional inhibitor discovery, demonstrating its utility in probing protein dynamics, identifying novel binding pockets, and investigating regulatory mechanisms. These results offer new insights into DHS function, hypusination dynamics, and the broader methodological advancements that CFS contributes to structural biology and protein regulation research.

The interaction of vanadium compounds of pharmaceutical interest with metal-transport proteins like human serum transferrin (hTF) is poorly understood. Direct structural evidence identifying vanadium binding sites on hTF is still lacking. Here, the X-ray structure of the adduct formed when the potential drug [V^IVO(acac)₂], with acac = acetylacetonato, reacts with human serum transferrin with Fe³⁺ bound at the C-lobe only (Fe_C-hTF) has been solved and compared with new structures of Fe_C-hTF used as controls. Structural analysis revealed the presence of a [V^V₂O₆]^2- anion that can be described as a divanadate(V) anion, [V^V₂O₇]^4-, that has one oxygen replaced by the phenolate oxygen of Tyr188. The two vanadium centers adopt tetrahedral geometry, consistent with V^V behavior. The binding does not alter the overall conformation of Fe_C-hTF that retains the open conformation of the N-lobe and the closed conformation of the C-lobe, remaining able to be recognized by the transferrin receptor.

Spherulites are spherical crystals that are polycrystalline assemblies of radially organized crystallites. Despite their wide prevalence and relevance to fields ranging from geology to medicine, the dynamics of spherulitic crystallization and the conditions required for such growth remain ill-understood. Here, we reveal the conditions for controlled spherulitic growth of sodium sulfate crystals from evaporating aqueous solutions mixtures of sulfate salts at room temperature. We reveal that divalent metal ions in the salt solutions induce spherulitic growth of sodium sulfate through non-classical nucleation and self-assembly of (nearly)-oriented nanocrystals. A key result is the very high viscosity (~ 111 Pa ⋅ s) of the highly supersaturated solutions at the onset of spherulite precipitation. This allows for slow dynamics that facilitates the formation of a large number of mesoscopic prenucleation clusters, that subsequently show diffusion-limited growth and assemble into the spherulitic shapes. The spherulites are found to be metastable structures that form in out-of-equilibrium conditions. As the supersaturation decreases during growth, Na₂SO₄ spherulites can also evolve into other shapes depending on the evaporation rate. These findings shed light on the conditions that govern spherulite formation and provide practical strategies for tuning their morphology.

The selectivity and affinity of numerous protein-protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Here we investigate how folding-on-binding of a protein IDR by small molecules is facilitated by synergestic exploitation of interactions with a folded protein region. To this end, the molecular driving forces that underpin ordering of the N-terminal intrinsically disordered 'lid' region of the oncoprotein MDM2 by the small molecule AM-7209 were elucidated by a combination of molecular dynamics simulations, calorimetry and NMR measurements. Strikingly, mutations of lid residues distant from the ligand-binding site modulate potency by up to three orders of magnitude. A key requirement for conversion of this IDR into an ordered motif is collective stabilisation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19 to overcome conformational entropy loss associated with folding of the IDR. Our findings underscore the crucial role that protein IDRs can play in drug-resistance mechanisms and expand strategies available to medicinal chemists for ligand optimisation endeavours.

Hydrogen-assisted dehydrochlorination process (HaDHC) is an attractive route for the production of fluorine-containing olefins under relatively mild conditions, so far lacking the highly efficient metal-based catalysts and their design strategy. Here, we report a nano-MgF₂ supported Pd-Ag catalyst with a tunable Pd dispersion, which is optimized by the Pd-Ag alloy degree in the fresh catalyst and subsequently in situ chlorination during the induction period of reaction. After the in situ restructuring process, the resulting Pd-Ag/nano-MgF₂ catalysts with atomically dispersed Pd sites exhibited an excellent catalytic performance for HaDHC of 1,1,1,2-tetrafluoro-2-chloropropane (HCFC-244bb) to 2,3,3,3-tetrafluoropropene (HFO-1234yf), the new-generation refrigerant, with a conversion of ca. 60% and HFO-1234yf selectivity of ca. 82% at 270 °C. Characterization results reveal that the Pd-Ag alloy degree in the fresh catalyst can be facilely tuned by changing the impregnation sequences for bimetallic precursors during catalyst preparation due to different metal-support interactions. Constructing a high Pd-Ag alloy degree offers a high in situ chlorination degree of the catalyst surface to finally get highly isolated Pd sites. Adsorption and computational results demonstrate that the chemisorbed hydrogen species on the single atom Pd sites (Pd-F and Pd-F₃ sites) boost the HFO-1234yf formation, while the spillover hydrogen species derived from the large Pd ensembles (Pd₆, Pd₇, and Pd₈ clusters) contribute to the formation of deep hydrogeneration product, 1,1,1,2-tetrafluoropropane (HFC-254eb).

Transient Receptor Potential Melastatin 3 (TRPM3) is a non-selective, Ca²⁺-permeable ion channel that plays a pivotal role in peripheral thermosensation and nociception. Moreover, gain-of-function variants in TRPM3 underlie a spectrum of neurodevelopmental and epileptic disorders in humans, indicating an important role of TRPM3 in the central nervous system. Oxidative stress contributes to various neurological disorders of both the central and peripheral nervous system, but it is unknown whether TRPM3 activity is altered by the cellular redox state. Here, we report a direct, bidirectional modification of TRPM3 channel activity by oxidizing and reducing agents. Our data demonstrate a profound effect of the redox state on the channel properties of TRPM3, including a robust shift in the response profile to pharmacology and temperature sensitivity. In addition, we identified two cysteine residues in the extracellular pore loop of TRPM3 that underlie the redox-control of the channel, due to the reversible formation of intra-subunit cysteine bridges. Taken together, these observations raise the hypothesis that TRPM3 could be modulated through an alternative mechanism, potentially affecting pathways involved in pain and neurological function.

Charged polymer interactions govern biological and technological processes by altering the structure and dynamics of surrounding water. Studying these interactions across a broad concentration range is challenging, particularly at submicromolar levels where traditional methods lack sensitivity or molecular resolution. Here, we investigate interactions between hyaluronan (HA), a biologically and technologically relevant polymer, and model oligopeptides-nonaarginine, nonalysine, and nonaglycine. By combining angle-resolved second harmonic scattering (AR-SHS), dynamic light scattering, nuclear magnetic resonance, and all-atom molecular dynamics simulations, we resolve the molecular-scale mechanisms and structure of HA-peptide interactions. Our findings reveal selective, multivalent binding between HA and cationic peptides, inducing solvent and solute restructuring and nanoscale clustering. Simulations provide atomic-level insight, elucidating the transient nature of the interactions and highlighting the distinctive behavior of arginine-rich peptides. Our approach, integrating AR-SHS with simulations and routine techniques, offers molecular insights into polymer mixtures and a foundation for future studies of dynamic supramolecular systems in soft materials.

Enzymatic recycling of polyethylene terephthalate (PET) has been recognized as an eco-friendly option for addressing the global plastic waste problem. Fully deciphering the catalytic mechanism is vital for designing high-performance enzymes. Here, we performed quantum mechanics/molecular mechanics molecular dynamics simulations to systematically explore the depolymerization mechanism of PET by the hydrolase LCC^ICCG. We demonstrate that both PET chain binding and product release require free energy barriers, whereas the rate-determining step corresponds to a catalytic process with a free energy barrier of 20.4 kcal·mol^-1. We also observe that the enzyme internal electric field varies dynamically throughout the catalytic process. Oriented external electric field analysis indicates that this "dynamic shift" stabilizes the transition state more than the reactant, thereby lowering the energy barrier. We anticipate that these insights will contribute to the rational engineering of PET hydrolases by optimizing their dynamic internal electric fields.