Receptor Mechanisms and Signaling

The Lysosome Surface is an Unappreciated Hub for Vasopressin V2 Receptor Signaling

The vasopressin V2 receptor activates G proteins and β-arrestins at the lysosomal surface before being degraded.

Structure of the Gq-coupled adhesion receptor ADGRL4, a GPCR implicated in cancer

The paper determines the cryo-EM structure of ADGRL4 coupled to Gq, showing weak Gq coupling and distinct interactions compared to other GPCRs, supporting its role in cancer.

Stabilized D2R G-protein coupled receptor oligomers identify multi-state β-arrestin complexes

This study identifies D2R receptor mutants that stabilize oligomers and show biased recruitment of β-arrestin-2, leading to altered signaling outcomes.

RareFoldGPCR: Agonist Design Beyond Natural Amino Acids

RareFoldGPCR designs peptide agonists using noncanonical amino acids to modulate GPCRs, validated experimentally for functional activity.

Deep Receptor Scanning Reveals General Sequence Constraints on GPCR Biosynthesis

The paper introduces a platform to characterize GPCR expression and uses machine learning to identify structural features affecting their biosynthesis.

GPR174 Antagonism: Structure, Function, and Dynamics

This study models GPR174 bound to an antagonist and compares its dynamics to LysoPS, revealing distinct ligand-specific mechanisms and potential for immunotherapeutic antagonists.

Dual-mode tethered intramolecular agonist-dependent mechanoactivation of the adhesion GPCR ADGRG1/GPR56

This study investigates the mechanotransduction mechanism of ADGRG1/GPR56, revealing a dual-mode activation process that does not require NTF-CTF dissociation and depends on the Stachel element.

GPR97/ADGRG3 is activated by its tethered peptide agonist and not by steroids to induce neutrophil polarization and migration

Artificial Brain Extracellular Fluid in Radioligand Binding Assays: Effects on Affinities of Ligands at Serotonin 5-HT7 Receptors

This study compares ligand affinities at 5-HT7 receptors using standard buffer vs. artificial brain extracellular fluid, finding that temperature and buffer composition significantly affect antagonist/inverse agonist affinities but not agonist affinity.

Time-resolved structures of β2-adrenergic receptor modulation by a photoswitchable beta-blocker

This study captures time-resolved structures of β2AR modulated by a photoswitchable beta-blocker, revealing conformational changes linked to ligand isomerization and receptor function.

Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators

This study uses molecular dynamics simulations to investigate how different ligands affect 5-HT2AR activation, finding that excessive activation causes hallucinations while modest activation may yield antidepressant effects.

Isoform-Dependent Loss- and Gain-of-Function of the Gαs K53N Variant in Human Disease

This study investigates the K53N mutation in Gs isoforms, revealing isoform-specific loss- and gain-of-function effects contributing to disease mechanisms in endocrine and cardiac tissues.

Cholesterol differentially modulates the activity of opioid and muscarinic receptors via common binding site

This study identifies a shared non-canonical cholesterol-binding site at TM6 in muscarinic and opioid receptors, with significant implications for drug development targeting tissue-specific GPCR modulation.

Deciphering molecular determinants of GPCR-G protein receptor interactions by complementary integrative structural biology methods

This study uses cryo-EM and HDX-MS to analyze GPBAR1-G protein interactions, revealing conformational dynamics and structural details of the complex.

Cryo-EM structure of a cell-free synthesized full-length human β1-adrenergic receptor in complex with Gs

The paper determines the cryo-EM structure of a full-length human β1-adrenergic receptor in complex with Gs, revealing structural insights into ICL3's role in G protein activation.

Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands

The paper explains how bivalent insulin receptor ligands act as antagonists or agonists based on the order of their binding sites, using cryo-EM structures.

Developing inhibitors of the guanosine triphosphate hydrolysis accelerating activity of Regulator of G protein Signaling-14

This paper identifies and validates non-covalent inhibitors of RGS14 GAP activity using structure-guided virtual screening and machine learning, showing improved potency and CNS penetration.

β1- and β2-adrenergic Receptor Haplotypes Regulate Therapeutic Responses to Placebo and the Biased Ligand β-blocker Bucindolol

This paper shows that β1- and β2-adrenergic receptor haplotypes influence responses to bucindolol and placebo in heart failure patients, with internalizing haplotypes providing protection and bucindolol being effective in internalization-resistant ones.

Myosin VI and B-arrestin synergistically regulate GIPR internalization and signaling

This study identifies a novel GIPR trafficking pathway involving myosin VI and β-arrestin, showing their synergistic role in receptor internalization, signaling, and insulin response in pancreatic beta cells.

Increased RAMP3 expression enhances GLP-1 mediated Glucose Stimulated Insulin Secretion in a Manner Dependent on Ca2+ Mobilisation

RAMP3 complexes with GLP-1R at the plasma membrane, shifts signalling toward Ca2+ mobilisation, and enhances insulin secretion in INS-1 832/3 cells; Ramp3 loss blunts GLP-1 responses in mice.

Amylin receptor subunit interactions are modulated by agonists and determine signaling

The paper investigates how amylin receptor subunit interactions are modulated by agonists and how these interactions influence cAMP signaling.

Aromatic amino acids in the orthosteric region regulate cannabinoid receptor 1 conformation transitions

This study investigates how aromatic amino acids in the orthosteric region of CB1 regulate conformational transitions using molecular dynamics simulations, revealing their roles in stabilizing active states and modulating receptor dynamics.

Computational Design of Soluble CCR8 Analogues with Preserved Antibody Binding

This paper computationally designs soluble CCR8 analogues that retain native antibody binding, achieving a 62% success rate with preserved structural and functional properties.

Molecular insights into ligand recognition and signaling of GPR99/OXGR1

This study presents cryo-EM structures of GPR99/OXGR1 with oxoglutarate and LTE4, revealing distinct binding sites and signaling mechanisms.

Molecular characterization of an adhesion GPCR signal transduction

This study investigates ADGRG1 activation mechanisms through mechanical and allosteric pathways, showing force direction determines signaling via GAIN domain dynamics and introducing engineered variants with tailored sensitivity.

Computational design of allosteric pathways reprograms ligand-selective GPCR signaling

This study designs GPCR variants with reprogrammed ligand-selective signaling using computational methods, showing sequence variations impact ligand potency and efficacy.

Tunable Bias Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C-Terminal Peptide Modifications and Allosteric Site Targeting

This study identifies AngII analogs with modified C-terminal peptides that selectively engage Gq or β-arrestin pathways, showing differential effects on cardiac function and blood pressure in rats.

XenoSignal: Investigating Intra- and Inter-Species Ligand-Receptor Interactions Using AlphaFold3

XenoSignal assesses ligand-receptor interactions across species using AlphaFold3 predictions to improve understanding of tumor-microenvironment crosstalk in xenograft models.

Go/z-biased coupling profile of the dopamine D3 receptor

The paper investigates the G protein coupling profile of dopamine D3 receptor, finding it selectively activates Go and Gz subtypes but not Gi proteins, with structural determinants identified.

GPCR Antagonism via Antibody-Mediated Rewiring of Receptor Trafficking and Degradation

This paper introduces GTACs, bispecific antibodies that selectively downregulate GPCRs via endocytosis and lysosomal degradation, showing high potency and selectivity for therapeutic targets.