Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 2, 2024

Abstract The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin or GPR109A, is a prototypical GPCR that plays central role in inhibition of lipolytic and atherogenic activities. Its activation results vasodilation linked to side-effect flushing associated with dyslipidemia drugs such niacin. GPR109A continues be target for developing potential therapeutics minimized response. Here, we present cryo-EM structures complex drugs, acipimox, non-flushing agonists, MK6892 GSK256073, recently approved psoriasis drug, monomethyl fumarate (MMF). These elucidate binding mechanism molecular basis activation, insights into biased signaling elicited by some agonists. structural framework allows us engineer mutants exhibit G-protein bias, therefore, our study may help structure-guided drug discovery efforts targeting this receptor.

Language: Английский

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The Structural Basis of the G Protein–Coupled Receptor and Ion Channel Axis

Current Research in Structural Biology, Journal Year: 2025, Volume and Issue: 9, P. 100165 - 100165

Published: Feb. 19, 2025

Sensory neurons play an essential role in recognizing and responding to detrimental, irritating, inflammatory stimuli from our surroundings, such as pain, itch, cough, neurogenic inflammation. The transduction of these physiological signals is chiefly mediated by G protein-coupled receptors (GPCRs) ion channels. binding ligands GPCRs triggers a signaling cascade, recruiting proteins or β-arrestins, which subsequently interact with channels (e.g., GIRK TRP channels). This interaction leads the sensitization activation channels, initiating neuron's protective mechanisms. review delves into complex interplay between that underpin processes, particular focus on structural biology enhancing comprehension. Through unraveling intricacies GPCR-ion channel axis, we aim shed light sophisticated intermolecular dynamics within pivotal membrane protein families, ultimately guiding development precise therapeutic interventions.

Language: Английский

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Insights into the Activation Mechanism of HCA1, HCA2, and HCA3

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on its clinical application has been limited adverse effects. Therefore, role HCA1 as a promising target for treatment lipolysis warrants further exploration. As HCAs exhibit high similarity when with diverse selective agonists, conserved yet unique activation mechanism remains undisclosed. Herein, we unveil cryo-electron microscopy structures 3,5-DHBA-HCA1-Gi signaling complex, acifran- MK6892-bound HCA2-Gi complexes, acifran-HCA3-Gi complex. Comparative analysis across reveals key residues in contributing to stabilization ligand-binding pocket. Furthermore, chimeric complexes mutational analyses identify that are pivotal HCA2 selectivity. Our findings elucidate critical structural insights into mechanisms ligand recognition within broaden our comprehension specificity binding HCA family.

Language: Английский

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Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication

Immune Network, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 1, 2025

Aromatic amino acid (AAA) metabolites, derived from tryptophan, phenylalanine, and tyrosine through coordinated host microbial metabolism, have emerged as critical modulators of immune function. We examine the complex journey AAAs dietary intake intestinal absorption metabolic transformation, highlighting crucial role host-microbe networks in generating diverse immunomodulatory compounds. This review provides a unique integrative perspective by mapping molecular mechanisms which these metabolites orchestrate responses. Through detailed analysis metabolite-receptor metabolite-transporter interactions, we reveal how specific recognition drives cell type-specific Our comprehensive examination signaling networks-from membrane receptor engagement to nuclear activation post-translational modifications- demonstrates same metabolite can elicit distinct functional outcomes different populations. The context-dependent nature interactions presents both challenges opportunities for therapeutic development, particularly inflammatory conditions where pathways are dysregulated. Understanding complexity regulatory remaining knowledge gaps is fundamental advancing metabolite-based strategies immune-mediated disorders.

Language: Английский

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Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(4), P. e3003126 - e3003126

Published: April 15, 2025

Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate or GPR81, is a class A G-protein-coupled with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response humans. HCAR1 highly expressed numerous types of cancer cells, where it participates controlling cell metabolism defense mechanisms, rendering an appealing target for therapy. However, the molecular basis HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures human HCAR2 complex Gi1 protein, which binds to subtype-specific agonist CHBA (3.16 Å) apo form (3.36 Å), agonists MK-1903 (2.68 SCH900271 (3.06 Å). Combined mutagenesis cellular functional assays, elucidate mechanisms underlying ligand recognition, activation, G protein coupling HCAR1. More importantly, residues that determine selectivity between are clarified. On this basis, further summarize structural features match orthosteric pockets HCAR2. These insights anticipated greatly accelerate development novel HCAR1-targeted drugs, offering promising avenue treatment various diseases.

Language: Английский

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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 25, 2024

Abstract A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with protein binding—and back – is revealed by a puzzle thirty novel 3D structures hydroxycarboxylic acid 2 (HCAR2) in complex eight different orthosteric and single agonist. HCAR2 sensor β-hydroxybutyrate, niacin certain anti-inflammatory drugs. Surprisingly, without on-target side effects bound very similarly completely occluded binding site. Thus, despite many we are still left pertinent need to understand molecular dynamics this similar systems.

Language: Английский

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Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114895 - 114895

Published: Oct. 19, 2024

Language: Английский

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Ligand recognition and activation mechanism of the alicarboxylic acid receptors

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168795 - 168795

Published: Sept. 1, 2024

Language: Английский

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Lactobacilli and lactic acid in maintaining and restoring women’s health

Reproductive health of woman, Journal Year: 2023, Volume and Issue: 8, P. 55 - 63

Published: Nov. 30, 2023

The review article presents modern data on the vaginal microbiota as a component of female microbiome in normal and pathological conditions. compositions different types community their role ensuring women’s health are described. It is emphasized that lactobacilli, including L. crispatus, gasseri, jensenii, vaginalis, iners, associated with healthy microbiota, while iners also related to transitional dysbiotic stages.All lactobacilli produce lactic acid, acetic acid hydrogen peroxide, maintain pH less than 4.5, inhibit growth pathogenic bacteria excessive Candida albicans and, therefore, protect against pathogens bacterial vaginosis candidiasis.The provides key microbicidal virulicidal factor immunomodulatory activity. colonization resistance vagina highlighted. importance states development adverse consequences for was analyzed.Existing methods treatment conditions described, which include such antibiotics metronidazole, clindamycin, estrogen therapy, boric acids, probiotics, transplantation microbiota. Traditional antibacterial therapy metronidazole or clindamycin does not always provide high efficacy long term, there rate recurrence cases candidiasis after treatment.Systemic use has significant side effects. New strategies help improve outcomes. probiotics can flora, increase number beneficial bacteria, reduce harmful further stability flora environment.The describes advantages probiotic, complex preparation includes most common, identical live concentration combination an effective local support preventive agent cervical

Language: Английский

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Structural insights into the engagement of lysophosphatidic acid receptor 1 with different G proteins

Journal of Structural Biology, Journal Year: 2024, Volume and Issue: unknown, P. 108164 - 108164

Published: Dec. 1, 2024

Language: Английский

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