Unraveling allostery within the angiotensin II type 1 receptor for Gα _q and β-arrestin coupling

Science Signaling, Journal Year: 2023, Volume and Issue: 16(797)

Published: Aug. 8, 2023

G protein–coupled receptors engage both proteins and β-arrestins, their coupling can be biased by ligands mutations. Here, to resolve structural elements mechanisms underlying effector the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of entire sequence with pharmacological profiling Gα q β-arrestin engagement mutant molecular dynamics simulations. We showed that AT1R involved a large number residues spread across receptor, whereas fewer regions contributed regulation. Residue stretches in transmembrane domain 4 conferred bias represented an important element for functional selectivity. Furthermore, identified allosteric small-molecule binding sites were enclosed communities produced signaling when mutated. Last, communication within emanating from site beyond orthosteric AngII-binding different including currently unresolved regions. Our findings reveal could harnessed design research purposes develop modulators.

Language: Английский

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Spatiotemporal GPCR signaling illuminated by genetically encoded fluorescent biosensors

Current Opinion in Pharmacology, Journal Year: 2023, Volume and Issue: 71, P. 102384 - 102384

Published: June 15, 2023

Language: Английский

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Structural biology of complement receptors

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 11, 2023

The complement system plays crucial roles in a wide breadth of immune and inflammatory processes is frequently cited as an etiological or aggravating factor many human diseases, from asthma to cancer. Complement receptors encompass at least eight proteins four structural classes, orchestrating complement-mediated humoral cellular effector responses coordinating the complex cross-talk between innate adaptive immunity. progressive increase understanding features main factors, activated proteolytic fragments, their assemblies have spurred renewed interest deciphering receptor complexes. In this review, we describe what currently known about biology complexes with natural agonists pharmacological antagonists. We highlight fundamental concepts gray areas where issues problems been identified, including current research gaps. seek offer guidance into information underlies therapeutic endeavors. Finally, also indicate believe are potential developments field.

Language: Английский

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Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor

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

Published: Feb. 13, 2024

Abstract G protein-coupled receptors (GPCRs) bind to different protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13 C methyl methionine and 19 F NMR, we investigate the agonist-bound active state β 1 AR its ternary complexes proteins in solution. We find receptor adopts very similar conformations. In contrast, full assumes a conformation differing from previously characterised activation intermediates or complexes. Assessing kinetics binding for proteins, increased affinity s results much faster association receptor. Consequently, suggest kinetic-driven gate between canonical secondary coupling arises differential favourability state.

Language: Английский

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Ligand‐dependent protein interactions of the juvenile hormone receptor captured in real time

FEBS Journal, Journal Year: 2023, Volume and Issue: 290(11), P. 2881 - 2894

Published: Jan. 7, 2023

Juvenile hormone (JH) signalling provides vital regulatory functions during insect development via transcriptional regulation of genes critical for the progression metamorphosis and oogenesis. Despite importance JH signalling, underlying molecular mechanisms remain largely unknown. Our current understanding pathway depends on static end‐point information suffers from lack time‐resolved data. Here, we have addressed dynamic aspect by monitoring in real time interactions receptor proteins. Use two tags that reconstitute a functional luciferase when proximity enabled us to follow rapid assembly heterodimer basic helix–loop–helix/Per‐Arnt‐SIM (bHLH‐PAS) proteins, methoprene‐tolerant (Met) taiman (Tai), upon specific binding Met. On similar timescale (minutes), dissociation Met‐Met complexes occurred, again strictly dependent Met interaction with agonist ligands. To resolve questions regarding role chaperone Hsp90/83 JHR complex formation, used same technique demonstrate Met‐Hsp83 persisted absence but readily dissociated Preincubation Hsp90 inhibitor geldanamycin showed protected degradation was produce active dimer Tai. Thus, appear be governed principles those regulating aryl hydrocarbon receptor, closest vertebrate homologue arthropod receptor.

Language: Английский

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Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4393 - 4393

Published: Feb. 23, 2023

Modulation of the CXCL12-CXCR4 signaling axis is utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among different currently available drugs that inhibit CXCR4 activation, motixafortide-a best-in-class antagonist this GPCR receptor-has exhibited promising results preclinical studies pancreatic, breast, lung cancers. However, detailed information on interaction mechanism motixafortide still lacking. Here, we characterize motixafortide/CXCR4 CXCL12/CXCR4 protein complexes by using computational techniques unbiased all-atom molecular dynamics simulations. Our microsecond-long simulations systems indicate agonist triggers changes associated with active-like conformations, while favors inactive conformations CXCR4. Detailed ligand-protein analysis indicates motixafortide's six cationic residues, all which established charge-charge interactions acidic residues. Furthermore, two synthetic bulky chemical moieties work tandem restrict important residues activation. not only elucidate interacts receptor stabilizes states, but also provide essential rationally design inhibitors preserve outstanding pharmacological features motixafortide.

Language: Английский

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Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

Cancers, Journal Year: 2023, Volume and Issue: 15(6), P. 1694 - 1694

Published: March 9, 2023

The roles played by the peptides belonging to tachykinin (neurokinin A and B) calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, calcitonin (CGRP)) families in cancer development are reviewed. structure dynamics of neurokinin (NK)-2, NK-3, CGRP receptors studied together with intracellular signaling pathways which they involved. These play an important role many cancers, such as breast cancer, colorectal glioma, lung neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder endometrial Ewing sarcoma, gastric liver melanoma, osteosarcoma, ovarian pancreatic prostate renal thyroid cancer. involved tumor proliferation, migration, metastasis, angiogenesis, lymphangiogenesis. Several antitumor therapeutic strategies, including receptor antagonists, discussed. main research lines be developed future mentioned.

Language: Английский

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A multiscale predictive digital twin for neurocardiac modulation

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 601(17), P. 3789 - 3812

Published: Aug. 1, 2023

Abstract Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of sympathetic increases cardiac output increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows rate. Importantly, imbalance in control has been implicated development arrhythmias failure. Understanding mechanisms effects a major challenge because synapses different regions result multiple changes to function. For example, on sinoatrial node (SAN) impact pacemaking, contractile cells alter contraction arrhythmia vulnerability. Here, we present multiscale neurocardiac modelling simulator tool that predicts effect efferent branches ANS SAN ventricular myocardium. The model includes layered representation reproduces firing properties measured experimentally. Model parameters are derived from experiments atomistic simulations. first prototype digital twin applied make predictions across all scales, subcellular signalling pacemaker frequency tissue level responses. We predict conditions under which induces proarrhythmia can be modified prevent or inhibit arrhythmia. In summary, constitutes predictive framework test guide high‐throughput prediction novel neuromodulatory therapy. image Key points A multi‐layered branches, each with sparse random intralayer connectivity, synaptic dynamics conductance based integrate‐and‐fire neurons generates patterns close agreement experiment. key feature computational connection between both cells, where modification drives initiation electrical signals cells. utilized atomic‐scale molecular simulations association dissociation rates noradrenaline β‐adrenergic receptor. Multiscale demonstrate how may increase proclivity used terminate arrhythmias. serves as step towards for predicting neuromodulation reduce disease.

Language: Английский

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Genetic variants of accessory proteins and G proteins in human genetic disease

Critical Reviews in Clinical Laboratory Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 22

Published: Jan. 1, 2025

We present a series of three articles on the genetics and pharmacogenetics G protein- coupled receptors (GPCR). In first article, we discuss genetic variants protein subunits accessory proteins that are associated with human phenotypes; in second build upon this to "G protein-coupled receptor (GPCR) gene disease" third survey pharmacogenomics". review processes ligand binding, GPCR activation, inactivation, trafficking membrane context disease resulting from pathogenic proteins. Pathogenic genes encoding α β examined diverse phenotypes. Variants modify or organize coupling have been disease; these include contribution regulator signaling (RGS) hypertension; role activator type III phenotypes such as hypoxia; variation at RGS10 short stature immunological compromise; involvement kinases (GRKs), GRK4, hypertension. Variation encode involved outlined changes structure function may be

Language: Английский

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Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 28, 2025

Language: Английский

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