Isobavachalcone inhibits α-synuclein fibrillogenesis and its Parkinson's disease variants, disassembles the mature fibrils and alleviates cellular toxicity.

The accumulation of α-Synuclein (α-Syn) aggregates into neuronal inclusions is a hallmark of Parkinson's disease (PD), making α-Syn a key target for PD therapeutics. Here, we demonstrate that the chalcone compound isobavachalcone (IBC) inhibits α-Syn aggregation and remodels mature fibrils into fragmented filaments. IBC exhibits dose-dependent inhibition of wild-type α-Syn and PD-linked mutants (E46K, H50Q, G51D and A53T) while effectively abrogating seeded fibrillization.

Molecular and functional profiling of Gαi as an intracellular pH sensor.

Heterotrimeric G proteins (Gα, Gβ and Gγ) act downstream of G-protein-coupled receptors (GPCRs) to mediate signaling pathways that regulate various physiological processes and human disease conditions. While human Gαi and its yeast homolog Gpa1 were previously postulated to function as intracellular pH sensors, the pH-sensing capabilities of Gαi and the underlying mechanism remain to be established. Our research shows that variations in pH significantly affect the structure and stability of Gαi-GDP.

Modulation of Photocatalytic CO Reduction by - Codoping Engineering of Single-Atom Catalysts.

Transition metal (TM) single-atom catalysts (SACs) have been widely applied in photocatalytic CO reduction. In this work, - codoping engineering is introduced to account for the modulation of photocatalytic CO reduction on a two-dimensional (2D) bismuth-oxyhalide-based cathode by using first-principles calculation. - codoping is established via the Coulomb interactions between the negatively charged TM SACs and the positively charged vacancy () in the dopant-defect pairs.

Molecular and Functional Profiling of Gαi as an Intracellular pH Sensor.

Heterotrimeric G proteins (Gα, Gβ and Gγ) act downstream of G-protein-coupled receptors (GPCRs) to mediate signaling pathways that regulate various physiological processes and human disease conditions. Previously, human Gαi and its yeast homolog Gpa1 have been reported to function as intracellular pH sensors, yet the pH sensing capabilities of Gαi and the underlying mechanism remain to be established. Herein, we identify a pH sensing network within Gαi, and evaluate the consequences of pH modulation on the structure and stability of the G-protein.

A newly predicted stable calcium argon compound bycalculations under high pressure.

High pressure can change the valence electron arrangement of the elements, and it can be as a new method for the emergence of unexpected new compounds. In this paper, the Ca-Ar compounds at 0-200 GPa are systematically investigated by using CALYPSO structure prediction methods combined with first principles calculations. The study of the Ca-Ar system can provide theoretical guidance for the exploration of new structures of inert elemental Ar compounds under high pressure.

Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.

Small GTPases including Ras, Rho, Rab, Arf, and Ran are omnipresent molecular switches in regulating key cellular functions. Their dysregulation is a therapeutic target for tumors, neurodegeneration, cardiomyopathies, and infection. However, small GTPases have been historically recognized as "undruggable".

Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for Alzheimer's disease pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease, especially at the early stages of the disease.

Facile construction of highly luminescent and biocompatible gold nanoclusters by shell rigidification for two-photon pH-edited cytoplasmic and imaging.

Gold nanoclusters (AuNCs), as a novel fluorescent material, have been extensively explored and developed for bioimaging because of their attractive advantages such as ultrasmall size, low toxicity and exceptional two-photon excitation properties. However, it still remains a challenge to produce water-soluble, biocompatible and ultrabright AuNCs. Herein, we report on a novel one-pot synthesis of highly luminescent and biocompatible AuNCs by using polyvinyl pyrrolidone (PVP), a water-soluble polymer, to rigidify the primary stabilizing layer (shell) that is composed of 6-aza-2-thiothymine (ATT) ligands bound to the particle.

Discovery of dual-target ligands binding to beta2-adrenoceptor and cysteinyl-leukotriene receptor for the potential treatment of asthma from natural products derived DNA-encoded library.

The design, synthesis, and discovery of dual-target compounds are considered as a promising strategy to develop new drugs with improved safety and efficacy compared with single-target drugs. This necessitates development of the methodologies that enable us to rapidly and accurately achieve the dual-target leads. Applying rosmarinic acid, 18β-glycyrrhetinic acid, rhein, and ferulic acid as template building blocks, we introduced the self-assembling DNA encoded technique to build the library containing 1,000 compounds.

Site-selective covalently immobilized alpha 1A adrenergic receptor for thermodynamic and extra-thermodynamic study of four ligands binding to the receptor by chromatographic methods.

Immobilized G protein-coupled receptor is a versatile tool to study ligand-receptor interactions. In this work, we synthesized the immobilized alpha 1A adrenergic receptor (α-AR), a GPCR subtype mediating smooth muscle contraction, through a site-selective covalent method that relies on the reaction between haloalkane dehalogenase tagged α-AR and macroporous silica gel coated with 6-chlorohexanoic acid. To investigate thermodynamic and extra-thermodynamic parameters for ligand binding, we utilized the covalently immobilized receptor as stationary phase to perform frontal analysis and injection-amount dependent analysis as well as compared with the random immobilization method.

Early-stage structure-based drug discovery for small GTPases by NMR spectroscopy.

Small GTPase or Ras superfamily, including Ras, Rho, Rab, Ran and Arf, are fundamental in regulating a wide range of cellular processes such as growth, differentiation, migration and apoptosis. They share structural and functional similarities for binding guanine nucleotides and hydrolyzing GTP. Dysregulations of Ras proteins are involved in the pathophysiology of multiple human diseases, however there is still a stringent need for effective treatments targeting these proteins.

Immobilized beta-adrenergic receptor: A powerful chromatographic platform for drug discovery and evaluation of drug-like property for natural products.

Drug discovery based on natural products like medicinal herbs remains challenging due to the technique limitations for rapidly screening and validating leads. To address the challenges, we employ the immobilized β- adrenergic recepotor (β-AR), an identified target of asthma, as the stationary phase in chromatographic column to screen compounds extracted from Stemonae Radix, Playtycodonis Radix, and Glycyrrhizae Radix et Rhizoma. To analyze binding properties of the extracted compounds to the immobilized receptors, we measured their retention behavior in the receptor chromatography and compared with six clinical asthma drugs.

Astroglial Connexins in Neurodegenerative Diseases.

Astrocytes play a crucial role in the maintenance of the normal functions of the Central Nervous System (CNS). During the pathogenesis of neurodegenerative diseases, astrocytes undergo morphological and functional remodeling, a process called reactive astrogliosis, in response to the insults to the CNS. One of the key aspects of the reactive astrocytes is the change in the expression and function of connexins.

Procyanidine resists the fibril formation of human islet amyloid polypeptide.

Human islet amyloid polypeptide (hIAPP) is widely studied due to its close correlation with the pathogenic mechanism of type II diabetes mellitus (T2DM). Bioflavonoids have been used in the neurodegeneration and diabetes studies. However, the structure-activity relationship remains unclear in many of these compounds.

Monoubiquitination of KRAS at Lysine104 and Lysine147 Modulates Its Dynamics and Interaction with Partner Proteins.

KRAS, a 21 kDa guanine nucleotide-binding protein that functions as a molecular switch, plays a key role in regulating cellular growth. Dysregulation of this key signaling node leads to uncontrolled cell growth, a hallmark of cancer cells. KRAS undergoes post-translational modification by monoubiquitination at various locations, including at lysine104 (K104) and lysine147 (K147).

A universal allosteric mechanism for G protein activation.

G proteins play a central role in signal transduction and pharmacology. Signaling is initiated by cell-surface receptors, which promote guanosine triphosphate (GTP) binding and dissociation of Gα from the Gβγ subunits. Structural studies have revealed the molecular basis of subunit association with receptors, RGS proteins, and downstream effectors.

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface.

RAS proteins function as highly regulated molecular switches that control cellular growth. In addition to regulatory proteins, RAS undergoes a number of posttranslational modifications (PTMs) that regulate its activity. Lysine 104, a hot spot for multiple PTMs, is a highly conserved residue that forms key interactions that stabilize the RAS helix-2(H2)/helix-3(H3) interface.

Correction: Identification of lysine methylation in the core GTPase domain by GoMADScan.

[This corrects the article DOI: 10.1371/journal.pone.

Identification of lysine methylation in the core GTPase domain by GoMADScan.

RAS is the founding member of a superfamily of GTPases and regulates signaling pathways involved in cellular growth control. While recent studies have shown that the activation state of RAS can be controlled by lysine ubiquitylation and acetylation, the existence of lysine methylation of the RAS superfamily GTPases remains unexplored. In contrast to acetylation, methylation does not alter the side chain charge and it has been challenging to deduce its impact on protein structure by conventional amino acid substitutions.

Site-Specific Immobilization of β-AR Using O-Benzylguanine Derivative-Functionalized Supporter for High-Throughput Receptor-Targeting Lead Discovery.

The past decade has witnessed the great promise of strategies for ligand discovery based on surface-immobilized GPCRs. We present here a method for preparation of immobilized GPCRs. Key features include covalent immobilization with high specificity and robust application in drug-receptor interaction analysis and ligand screening.

Rationally designed carbohydrate-occluded epitopes elicit HIV-1 Env-specific antibodies.

An array of carbohydrates masks the HIV-1 surface protein Env, contributing to the evasion of humoral immunity. In most HIV-1 isolates 'glycan holes' occur due to natural sequence variation, potentially revealing the underlying protein surface to the immune system. Here we computationally design epitopes that mimic such surface features (carbohydrate-occluded neutralization epitopes or CONE) of Env through 'epitope transplantation', in which the target region is presented on a carrier protein scaffold with preserved structural properties.

O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3.

Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked β-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP).

Regulation of heteronuclear Pt-Ru complexes on the fibril formation and cytotoxicity of human islet amyloid polypeptide.

The deposition of human islet amyloid polypeptide (hIAPP) is considered as a causative factor of type 2 diabetes mellitus (T2DM). Developing effective inhibitors against the fibril formation of hIAPP is a potential way to treat T2DM. Recent studies indicate that various metal complexes including homo-binuclear Ru complexes can inhibit hIAPP aggregation.

RNA-Seq analysis of interferon inducible p204-mediated network in anti-tumor immunity.

p204, a murine member of the interferon-inducible p200 protein family, and its human analogue, IFI16, have been shown to function as tumor suppressors in vitro, but the molecular events involved, in particular in vivo, remain unclear. Herein we induced the Lewis Lung carcinoma (LLC) murine model of human lung cancer in p204 null mice (KO) and their control littermates (WT). We compared the transcriptome in spleen from WT and p204 KO mice using a high-throughput RNA-sequencing array.