G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 9, 2024

Abstract G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects allosteric effects, biased signaling balanced signaling, characterize complexity GPCR dynamic features. In this study, we first review structural advancements, activation mechanisms, functional diversity GPCRs. We then focus on discovery by revealing detailed drug-target interactions underlying mechanisms drugs approved US Food Drug Administration past five years. Particularly, up-to-date analysis is performed available structures complexed with synthetic small-molecule modulators to elucidate key receptor-ligand mechanisms. Finally, highlight how widespread GPCR-druggable sites can guide structure- mechanism-based design propose prospects designing bitopic ligands for future therapeutic potential targeting receptor family.

Language: Английский

---

Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: 20(6), P. 349 - 365

Published: Feb. 29, 2024

Language: Английский

---

ASD2023: towards the integrating landscapes of allosteric knowledgebase

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D376 - D383

Published: Oct. 23, 2023

Abstract Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of most direct and efficient ways to fine-tune macromolecular function. The Database (ASD; accessible online http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 provide comprehensive information on regulation. In recent years, allostery seen sustained growth wide-ranging applications in life sciences, basic research new therapeutics development, while also elucidating emerging obstacles across stages. To overcome these challenges maintain high-quality data center services, novel features were curated ASD2023 update: (i) 66 589 potential sites, covering > 80% human proteome constituting pocketome; (ii) 748 protein–protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies PPI-targeted drug discovery; (iii) ‘Allosteric Hit-to-Lead,’ a pioneering dataset providing panoramic views 87 well-defined hits 6565 leads (iv) 456 dualsteric for exploring simultaneous regulation sites. Meanwhile, maintains significant foundational data. Based efforts, knowledgebase progressively evolving towards integrated landscape, facilitating advancements target identification, mechanistic exploration discovery.

Language: Английский

---

Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence

Journal of Endocrinology, Journal Year: 2024, Volume and Issue: 261(3)

Published: April 3, 2024

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon a key metabolic regulator, and its actions include the reduction of fat through direct indirect means. Chronic glucagon signalling deficiency hyperaminoacidaemia, hyperglucagonaemia increased circulating levels glucagon-like peptide (GLP-1) fibroblast growth factor 21 (FGF-21). Reduction in activity decreases hepatic amino acid triglyceride catabolism; effects improved glucose tolerance, plasma cholesterol fat. Conversely, infusion healthy volunteers leads to output, decreased acids urea production, energy expenditure. Patients share many hormonal characteristics models deficiency, suggesting that they could be resistant glucagon. Although studies patients obesity and/or MASLD, some evidence expected effect on catabolism may attenuated. Taken together, this supports notion resistance exists contribute pathogenesis MASLD. Further warranted investigate metabolism

Language: Английский

---

Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5

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

Published: Aug. 30, 2024

Two-thirds of signaling hormones and one-third approved drugs exert their effects by binding modulating the G protein-coupled receptors (GPCRs) activation. While activation mechanism for monomeric GPCRs has been well-established, little is known about in dimeric form. Here, combining transition pathway generation, extensive atomistic simulation-based Markov state models, experimental assays, we reveal an asymmetric, stepwise millisecond allosteric metabotropic glutamate receptor subtype 5 (mGlu5), obligate class C GPCR. The dynamic picture presented that agonist induces ectodomains compaction, amplified precise association cysteine-rich domains, ultimately loosely bringing intracellular 7-transmembrane (7TM) domains into proximity establishing asymmetric TM6-TM6 interface. active inter-domain interface enhances intra-domain flexibility, triggering micro-switches crucial downstream signal transduction. Furthermore, show positive modulator stabilizes both 7TM open, extended ICL2 conformation. This stabilization leads to formation a pseudo-cavity composed ICL2, ICL3, TM3, C-terminus, which facilitates protein coordination. Our strategy may be generalizable characterizing events other systems. Activation form remains enigmatic. authors present characterization mGlu5, GPCR, suggesting mechanism.

Language: Английский

---

Allosterism in the adenosine A_2A and cannabinoid CB₂ heteromer

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: July 23, 2024

Abstract Background and Purpose Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand‐binding or protein–protein interactions with another GPCR. We have studied the influence of dimer interface on allosteric properties A 2A receptor CB 2 heteromer. Experimental Approach evaluated cAMP production, phosphorylation signal‐regulated kinases (pERK1/2), label‐free dynamic mass redistribution, β‐arrestin recruitment bimolecular fluorescence complementation assays in absence presence synthetic peptides disrupt formation Molecular simulations provided converging evidence heteromeric influences R–CB R Key Results Apo blocks agonist‐induced signalling R. The disruptive peptides, amino acid sequence transmembrane (TM) 6 R, facilitate activation, suggesting allosterically prevents outward movement TM G protein binding. Significantly, binding selective antagonist SCH 58261 to also facilitated activation Conclusions Implications It proposed heteromer contains distinct dimerization interfaces govern its functional properties. molecular between protomers interconverted from apo agonist‐bound blocking mainly 1/7 antagonist‐bound facilitating independent opening intracellular cavities These novel results shed light different type extend repertoire GPCR signalling.

Language: Английский

---

Glucagon and Its Receptors in the Mammalian Heart

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12829 - 12829

Published: Aug. 15, 2023

Glucagon exerts effects on the mammalian heart. These include alterations in force of contraction, beating rate, and changes cardiac conduction system axis. The glucagon vary according to species, region, age, concomitant disease. Depending species region studied, contractile can be robust, modest, or even absent. is detected heart might act with an autocrine paracrine effect receptors. levels blood receptor change disease simultaneous drug application. signal via receptors but, albeit less potently, also glucagon-like-peptide-1-receptors (GLP1-receptors). a species- region-dependent fashion. Small molecules antibodies as antagonists receptors, which may become additional treatment option for diabetes mellitus. Hence, novel review role heart, eye mouse human appears relevant. Mouse hearts are addressed here because they easily genetically modified generate mice that serve models better studying receptor.

Language: Английский

---

All over or overall – Do we understand allostery?

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 83, P. 102724 - 102724

Published: Oct. 27, 2023

Allostery is probably the most important concept in regulation of cellular processes. Models to explain allostery are plenty. Each sheds light on different aspects but their entirety conveys an ambiguous feeling comprehension and disappointment. Here, I discuss popular models, roots, similarities, limitations. All them thermodynamic models. Naturally this bears a certain degree redundancy, which forms center review. After sixty years, many questions remain unanswered, mainly because our human longing for causality as base understanding not satisfied by thermodynamics alone. A description terms pathways, i.e., temporal chain events, has been-, still is-, missing piece puzzle.

Language: Английский

---

Distinct Activation Mechanisms of CXCR4 and ACKR3 Revealed by Single-Molecule Analysis of their Conformational Landscapes

Published: March 11, 2025

The canonical chemokine receptor CXCR4 and atypical ACKR3 both respond to CXCL12 but induce different effector responses regulate cell migration. While couples G proteins directly promotes migration, is protein-independent scavenges extracellular levels maintain responsiveness, thereby indirectly influencing receptors also have distinct activation requirements. only responds wild-type sensitive mutation of the chemokine. By contrast, recruits GPCR kinases (GRKs) β-arrestins promiscuously CXCL12, variants, other peptides proteins, relatively insensitive mutation. To investigate role conformational dynamics in pharmacological behaviors ACKR3, we employed single-molecule FRET track discrete states real-time. data revealed that apo-CXCR4 preferentially populates a high-FRET inactive state, while apo-ACKR3 shows little preference high transition probabilities among multiple inactive, intermediate active conformations, consistent with its propensity for activation. Multiple active-like conformations are populated response agonists, compared single active-state. This markedly landscapes suggest may be achieved by broader distribution than CXCR4. Much heterogeneity linked residue differs between dynamic properties underly inability form productive interactions would drive signaling.

Language: Английский

---

Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108846 - 108846

Published: April 1, 2025

Class B G protein-coupled receptors (GPCRs) are a subfamily of 15 peptide hormone with diverse roles in physiological functions and disease pathogenesis. Over the past decade, several novel therapeutics targeting these have been approved for conditions like migraine, diabetes, obesity, many which ground-breaking first-in-class. Most agonist analogues modified endogenous sequences to enhance receptor activation or stability. Several small molecule monoclonal antibody antagonists also late-stage development. Differences sequence structure therapeutic ligands lead distinct signalling profiles, including biased behaviour inhibition specific pathways. Understanding this pharmacology offers unique development opportunities improving efficacy reducing adverse effects. This review summarises current knowledge on ligand bias class GPCR drugs, highlights strategies refine exploit their pharmacological discusses key considerations related structure, localisation, regulation developing new therapies.

Language: Английский

---