Receptor Mechanisms and Signaling

Structural Basis of Asymmetric Class C GPCR activation and distinct Gq coupling induced by force stimulation

This paper reveals how mechanical force activates mGlu2 through a unique cis mechanism and induces distinct Gq coupling, providing structural insights and a chemical toolset for modulating mechanosensitive GPCRs.

Deep Learning Reveals Endogenous Sterols as Allosteric Modulators of the GPCR-Gα Interface

The paper identifies endogenous sterols as intracellular allosteric modulators of the GPCR-Gα interface using a deep learning toolkit and experimental validation.

Temporally Resolved and Interpretable Machine Learning Model of GPCR Conformational Transition

This paper develops an interpretable machine learning model to identify residue communities involved in GPCR conformational transitions, with applications to dopamine receptor subtype-specific drug design.

Selective Activation of GPCRs: Molecular Dynamics Shows Siponimod Binds but Fails to Activate S1PR2 Unlike S1PR1

This study uses molecular dynamics to show that Siponimod binds both S1PR1 and S1PR2 but only activates S1PR1 by inducing conformational changes absent in S1PR2.

Differential effects of sodium on agonist-induced conformational transitions and signaling at μ and κ opioid receptors

The paper examines how sodium ions differentially modulate agonist-induced conformational changes and signaling at μ and κ opioid receptors, revealing opposing effects between the two receptor types.

Structure of an LGR dimer - an evolutionary predecessor of glycoprotein hormone receptors

The paper presents the cryo-EM structure of a nematode LGR dimer, providing insights into the evolution and function of glycoprotein hormone receptors.

G protein-coupled receptor diversity and evolution in the closest living relatives of Metazoa

The paper catalogs GPCRs, G proteins, and regulators in choanoflagellates, revealing expanded diversity and conserved families, with implications for metazoan GPCR evolution.

Reverse-engineering B-Arrestin Bias in the d-Opioid Receptor

The paper uses molecular dynamics simulations to study signaling bias in the delta-opioid receptor, identifying structural determinants of beta-arrestin recruitment and demonstrating how mutations can reshape signaling profiles.

GPR17 structure and agonism with small molecules and oxysterols

This study presents cryo-EM structures of GPR17 with ligands and shows orthosteric and allosteric binding mechanisms, suggesting alternative approaches for drug discovery.

Nuclear α1A-Adrenergic Receptor Regulation of cAMP Production by an Inside-Out MAP Kinase Signaling Pathway in Cardiac Myocytes

The paper shows that nuclear α1A-adrenergic receptors inhibit βAR-mediated cAMP production via an inside-out MAPK signaling pathway in cardiac myocytes, revealing a novel mechanism of sympathetic signaling interaction.

The Adhesion GPCR ADGRL2 engages Gα13 to Enable Epidermal Differentiation

The paper identifies ADGRL2's role in epidermal differentiation through Gα13 activation and structural interactions, using CRISPR, Perturb-seq, and cryo-EM.

FDA drug repurposing uncovers modulators of dopamine D2 receptor localization via disruption of the NCS-1 interaction

The paper identifies FDA-approved drugs that disrupt the NCS-1/D2R interaction, modulating D2R localization without affecting its signaling.

Structural basis and physiological significance of non-canonical Gs coupling to the prototypical Gi-coupled melatonin MT1 receptor

The paper shows MT1, a Gi-coupled receptor, can also couple to Gs proteins, activates the Gs/cAMP pathway under long-term melatonin exposure, and presents the first solved structure of a Gi-coupled receptor-Gs complex.

Single-molecule detection of transient dimerization of opioid receptors 2: Heterodimer blockage reduces morphine tolerance

The paper uses single-molecule imaging to study opioid receptor heterodimerization and shows that blocking MOR-DOR heterodimers reduces morphine tolerance in mice.

Measuring serotonin binding to its receptors in vitro via charge transfer to ANAP

This paper introduces a fluorescence-based method to measure serotonin binding to its receptors in vitro using ANAP, showing concentration-dependent quenching and validating it with electrophysiology.

GABA-independent activation of GABAB receptor by mechanical forces

This paper shows that GABAB receptors can be activated by mechanical forces without GABA, through integrin-GB1 interactions leading to receptor activation and astrocyte remodeling.

Single-molecule detection of transient dimerization of opioid receptors 1: Homodimers' effect on signaling and internalization

This study uses single-molecule imaging to show that opioid receptors form transient homodimers, with distinct functional effects on signaling and internalization depending on the receptor subtype.

Serotonin 5-HT2C receptor as a cellular target of PI3K inhibitor LY294002 and its analog LY303511

This study shows that LY294002 and LY303511 affect serotonin-induced Ca2+ signaling via distinct mechanisms involving the 5-HT2C receptor, suggesting off-target effects beyond their intended PI3K inhibition.

Glucagon-like peptide-1 receptor C-terminal tail phosphorylation determines signalling responses from pancreatic β-cells

This study shows that phosphorylation of specific C-terminal serine doublets in the GLP-1R is critical for receptor signaling in β-cells, with basal phosphorylation influencing receptor dynamics and signaling outcomes.

Beyond the 1:1 Ligand-Protein Paradigm: An In Silico Assay for Competitive Ligand Binding

The paper introduces a coarse-grained MD approach to simulate competitive ligand binding at the adenosine A2A receptor, revealing cooperative mechanisms in ligand competition.

Atypical activation and molecular glue-like dimerization mechanism of an intrinsically-biased chemokine receptor

This study reveals an atypical activation mechanism of CXCR7, identifies its role as an opioid receptor, and highlights potential for novel pain therapeutics.

Structural Insights into Selective and Dual Antagonism of EP2 and EP4 Prostaglandin Receptors

The paper presents cryo-EM structures of EP2 and EP4 receptors with antagonists, revealing structural differences that explain selectivity and binding modes.

The free fatty acid 2 receptor regulates the activation potency of C5a and the sensitivity to the antagonist avacopan

This study shows that the free fatty acid 2 receptor modulates C5a receptor signaling, enhancing NADPH oxidase activation and reducing the effect of the antagonist avacopan.

A simple theory to explain super-additivity of highly similar drug combinations

The paper presents a thermodynamic model explaining super-additivity in similar drug combinations, with implications for cysteine-derived compounds and opioid withdrawal treatment.

Design of allosteric modulators that change GPCR G protein subtype selectivity

This study designs allosteric modulators that alter GPCR G protein subtype selectivity by targeting the receptor-transducer interface, demonstrating predictable mechanisms for rational drug design.

Balancing Rigidity and Flexibility: Optimised 4-(Hexyloxy)benzoate Antagonists with Enhanced Affinity and Tuneable Duration at Muscarinic Receptors

This study synthesizes and evaluates 4-(hexyloxy)benzoate derivatives to optimize muscarinic receptor antagonists, finding that rigid groups increase affinity but reduce duration, while flexible analogues balance potency and residence time.

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling

The paper identifies multiple allosteric sites on the D1 dopamine receptor that allow synergistic enhancement of GPCR signaling through combined positive allosteric modulators.

A biased allosteric modulator functions as a molecular glue to induce β2AR dimerization

The paper shows that AP-7-168 induces β2AR dimerization by acting as a molecular glue, revealing a new allosteric mechanism for GPCR modulation.

The allosteric mechanism of G-protein-coupled receptors is induced fit, not conformational selection

This paper investigates the allosteric mechanism of GPCRs, finding that both peptide- and small-molecule-activated GPCRs use an induced-fit mechanism rather than conformational selection.

Hydration Network Drives Activation and G Protein Selectivity in GPR174

This study identifies a hydration network in GPR174 that drives receptor activation and G protein selectivity through structural and functional analyses.