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Nature Communications Aug 2023MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report...
MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal "RF/RY" motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the GXPFGXF/W motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling.
Topics: Humans; Cytoplasm; Cytosol; Ligands; Pruritus; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 37591889
DOI: 10.1038/s41467-023-40705-z -
Trends in Pharmacological Sciences Dec 2023Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity.... (Review)
Review
Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 'selectivity hotspots', that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive 'off-target' contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects.
Topics: Humans; Receptors, G-Protein-Coupled; Serotonin; Ligands; Binding Sites; Migraine Disorders
PubMed: 37914598
DOI: 10.1016/j.tips.2023.09.012 -
Journal of Lipid Research Aug 2023Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and... (Review)
Review
Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation function. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid-ligand binding allosterically regulates the conformation of the LBD, regulating transcriptional coregulator recruitment and thus nuclear receptor function. These structural studies have aided the development of several FDA-approved drugs, highlighting the importance of understanding the structure-function relationships between lipids and nuclear receptors. However, there are few published descriptions of full-length nuclear receptor structure and even fewer descriptions of how lipids might allosterically regulate full-length structure. Here, we examine multidomain interactions based on the published full-length nuclear receptor structures, evaluating the potential of interdomain interfaces within these nuclear receptors to act as inducible sites of allosteric regulation by lipids.
Topics: Allosteric Regulation; Binding Sites; Ligands; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Lipids
PubMed: 37356665
DOI: 10.1016/j.jlr.2023.100406 -
Molecules (Basel, Switzerland) Aug 2023G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active... (Review)
Review
G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling-proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling.
Topics: Signal Transduction; Cell Membrane; Rhodopsin; Receptors, Ghrelin; Analgesics, Opioid; Ligands
PubMed: 37687205
DOI: 10.3390/molecules28176375 -
Nature Communications Nov 2023Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid,...
Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.
Topics: Humans; Carboxylic Acids; Ligands; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 37932263
DOI: 10.1038/s41467-023-42764-8 -
Nucleic Acids Research Jan 2024Riboswitches are regulatory elements found in the untranslated regions (UTRs) of certain mRNA molecules. They typically comprise two distinct domains: an aptamer domain...
Riboswitches are regulatory elements found in the untranslated regions (UTRs) of certain mRNA molecules. They typically comprise two distinct domains: an aptamer domain that can bind to specific small molecules, and an expression platform that controls gene expression. Riboswitches work by undergoing a conformational change upon binding to their specific ligand, thus activating or repressing the genes downstream. This mechanism allows gene expression regulation in response to metabolites or small molecules. To systematically summarise riboswitch structures and their related ligand binding functions, we present Ribocentre-switch, a comprehensive database of riboswitches, including the information as follows: sequences, structures, functions, ligand binding pockets and biological applications. It encompasses 56 riboswitches and 26 orphan riboswitches from over 430 references, with a total of 89 591 sequences. It serves as a good resource for comparing different riboswitches and facilitating the identification of potential riboswitch candidates. Therefore, it may facilitate the understanding of RNA structural conformational changes in response to ligand signaling. The database is publicly available at https://riboswitch.ribocentre.org.
Topics: Ligands; Nucleic Acid Conformation; Regulatory Sequences, Nucleic Acid; Riboswitch; Signal Transduction; Databases, Nucleic Acid
PubMed: 37855663
DOI: 10.1093/nar/gkad891 -
International Journal of Molecular... May 2023Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and... (Review)
Review
Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and will contribute to drug discovery and biomedical application. An important issue involved is how the receptor-ligand binding responds to mechanical stimuli. This review aims to provide an overview of the current understanding of the effect of several representative mechanical factors, such as tension, shear stress, stretch, compression, and substrate stiffness on receptor-ligand binding, wherein the biomedical implications are focused. In addition, we highlight the importance of synergistic development of experimental and computational methods for fully understanding the in situ receptor-ligand binding, and further studies should focus on the coupling effects of these mechanical factors.
Topics: Mechanotransduction, Cellular; Ligands; Stress, Mechanical; Pressure
PubMed: 37240408
DOI: 10.3390/ijms24109062 -
Current Opinion in Cell Biology Dec 2023The mechanical regulation of Notch signaling is an emerging area of interest in cell biology. Notch is essential in many physiological processes in which mechanical... (Review)
Review
The mechanical regulation of Notch signaling is an emerging area of interest in cell biology. Notch is essential in many physiological processes in which mechanical stress plays an important role. This review provides an overview of the mechanoregulation of Notch signaling in multiple steps of the pathway. First, we discuss the current knowledge on the direct mechanoregulation of Notch receptor maturation and localization to the membrane and the effect of mechanical stress on the Notch components. Next, we explore how ligand-receptor interactions and membrane dynamics are possible subjects to mechano-regulation, emphasizing the role of cytoskeletal interactions, membrane stiffness, and endocytic complex formation. We further delve into the necessity of tension generation for negative regulatory region (NRR) domain unfolding, facilitated by ligand endocytosis and other microforces. Additionally, we examine the indirect mechano-regulation of S2 and S3 cleavages. Finally, we discuss the mechanoregulation of the Notch intracellular domain (NICD) trafficking and nuclear entry and the impact of mechanical stress on heterochromatin dynamics and nuclear NICD interactions. This review aims to draw attention to the intricate interplay between mechanical cues and Notch signaling regulation, offering novel insights into the multifaceted nature of cellular mechanobiology.
Topics: Humans; Ligands; Signal Transduction; Receptors, Notch
PubMed: 37783031
DOI: 10.1016/j.ceb.2023.102244 -
Frontiers in Endocrinology 2023Gonadotropins regulate reproductive functions by binding to G protein-coupled receptors (FSHR and LHCGR) expressed in the gonads. They activate multiple, cell-specific... (Review)
Review
Gonadotropins regulate reproductive functions by binding to G protein-coupled receptors (FSHR and LHCGR) expressed in the gonads. They activate multiple, cell-specific signalling pathways, consisting of ligand-dependent intracellular events. Signalling cascades may be modulated by synthetic compounds which bind allosteric sites of FSHR and LHCGR or by membrane receptor interactions. Despite the hormone binding to the orthosteric site, allosteric ligands, and receptor heteromerizations may reshape intracellular signalling pattern. These molecules act as positive, negative, or neutral allosteric modulators, as well as non-competitive or inverse agonist ligands, providing a set of new compounds of a different nature and with unique pharmacological characteristics. Gonadotropin receptor allosteric modulation is gathering increasing interest from the scientific community and may be potentially exploited for clinical purposes. This review summarizes the current knowledge on gonadotropin receptor allosteric modulation and their potential, clinical use.
Topics: Drug Inverse Agonism; Ligands; Receptors, Gonadotropin; Signal Transduction; Gonads
PubMed: 37305033
DOI: 10.3389/fendo.2023.1179079 -
Science (New York, N.Y.) Aug 2023In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information in a manner analogous to...
In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information in a manner analogous to how transistors control information flow in computing devices. Designing proteins with two distinct but fully structured conformations is a challenge for protein design as it requires sculpting an energy landscape with two distinct minima. Here we describe the design of "hinge" proteins that populate one designed state in the absence of ligand and a second designed state in the presence of ligand. X-ray crystallography, electron microscopy, double electron-electron resonance spectroscopy, and binding measurements demonstrate that despite the significant structural differences the two states are designed with atomic level accuracy and that the conformational and binding equilibria are closely coupled.
Topics: Crystallography, X-Ray; Ligands; Protein Engineering; Protein Conformation
PubMed: 37590357
DOI: 10.1126/science.adg7731