Ligand recognition and G-protein coupling of trace amine receptor TAAR1.

Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.

Cryo-EM structures of human GPR34 enable the identification of selective antagonists.

GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and Gi protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.

Research Progress of the Biosynthesis of Natural Bio-Antibacterial Agent Pulcherriminic Acid in Bacillus.

Pulcherriminic acid is a cyclic dipeptide found mainly in Bacillus and yeast. Due to the ability of pulcherriminic acid to chelate Fe3+ to produce reddish brown pulcherrimin, microorganisms capable of synthesizing pulcherriminic acid compete with other microorganisms for environmental iron ions to achieve bacteriostatic effects. Therefore, studying the biosynthetic pathway and their enzymatic catalysis, gene regulation in the process of synthesis of pulcherriminic acid in Bacillus can facilitate the industrial production, and promote the wide application in food, agriculture and medicine industries. After initially discussing, this review summarizes current research on the synthesis of pulcherriminic acid by Bacillus, which includes the crystallization of key enzymes, molecular catalytic mechanisms, regulation of synthetic pathways, and methods to improve efficiency in synthesizing pulcherriminic acid and its precursors. Finally, possible applications of pulcherriminic acid in the fermented food, such as Chinese Baijiu, applying combinatorial biosynthesis will be summarized.

Targeting adverse effects of antiseizure medication on offspring: current evidence and new strategies for safety.

INTRODUCTION: For women with epilepsy of reproductive age, antiseizure medications (ASMs) are associated with an increased risk of offspring malformations. There are safety concerns for most anti-seizure medications in the perinatal period, and there is a clear need to identify safe medications. ASMs must transport through biological barriers to exert toxic effects on the fetus, and transporters play essential roles in trans-barrier drug transport. Therefore, it is vital to understand the distribution and properties of ASM-related transporters in biological barriers. AREAS COVERED: This study reviews the structure, transporter distribution, and properties of the blood-brain, placental, and blood-milk barrier, and summarizes the existing evidence for the trans-barrier transport mechanism of ASMs and standard experimental models of biological barriers. EXPERT OPINION: Ideal ASMs in the perinatal period should have the following characteristics: 1) Increased transport through the blood-brain barrier, and 2) Reduced transport of the placental and blood-milk barriers. Thus, only low-dose or almost no antiseizure medication could enter the fetus's body, which could decrease medication-induced fetal abnormalities. Based on the stimulated structure and molecular docking, we propose a development strategy for new ASMs targeting transporters of biological barriers to improve the perinatal treatment of female patients with epilepsy.

Structure, function and drug discovery of GPCR signaling.

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.

Research status of Bacillus phytase.

Phytic acid is abundant in seeds, roots and stems of plants, it acts as an anti-nutrient in food and feed industry, since it affects the absorption of nutrients by humans and monogastric animals. Furthermore, phosphorus produced through its decomposition by microorganisms can cause environmental pollution. Phytase degrades phytic acid generating precursors of inositol that can be used in clinical practice; in addition, phytase treatment can minimize the anti-nutritional effect of phytic acid. The use of phytase synthesized from Bacillus is more advantageous due to its high activity. Additionally, its good heat resistance under neutral conditions greatly fills the gap of commercial utilization of acid phytase. In this review, we summarize the latest research results on Bacillus phytase, including its physiological and biochemical characteristics, molecular structure information, calcium effects on its catalytic activity and stability, its catalytic mechanism and molecular modification.