Receptor Mechanisms and Signaling

Allostery between distant structural regions dictates selectivity in GPCR:G protein coupling.

The paper uses machine learning and simulations to show that distant residue interactions in the G protein core influence GPCR selectivity and can be engineered to change signaling preferences.

Discovery and dynamic pharmacology of μ-opioid receptor positive allosteric modulators

This study discovers μ-opioid receptor positive allosteric modulators (PAMs) and investigates their dynamic mechanism of action to enhance opioid agonist activity while reducing side effects.

Beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy

The paper reveals how beta-arrestin 1 activates Src kinase via two distinct SH3 domain interactions, using cryo-EM to show structural mechanisms of beta-arrestin-mediated signaling.

MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants

This study identifies shared molecular mechanisms by which MRAP2 regulates GPCR signaling and shows that obesity-associated variants disrupt these mechanisms.

Conformational biosensors delineate endosomal G protein regulation by GPCRs

This study investigates how GPCRs regulate G protein activity on endosomes using conformational biosensors, finding that endocytosis is required for active Gs production on endosomes.

Free Fatty Acid Receptor 2 Allosterism is Defined By Cellular Context

This study investigates FFA2R allosterism across cell models, showing pathway-selective modulation and highlighting Ca2+ mobilization and ROS as therapeutic readouts.

Structural Dynamics of the Dopamine D2 Receptor with a Non-Basic Ligand

The paper presents a cryo-EM structure of the dopamine D2 receptor bound to a non-basic ligand, revealing structural dynamics and binding energy landscapes that explain subtype selectivity.

Order of Message and Address Domain Engagement Determines Productive β-Endorphin Binding to the μ-Opioid Receptor

The paper uses molecular simulations to show that address-domain engagement before message-domain binding increases the success rate of β-endorphin binding to the μ-opioid receptor.

Computational design of constitutively active mutants of Dopamine D2 receptor inspired by ligand-independent activation mechanisms

The paper identifies a constitutively active mutant of the dopamine D2 receptor using computational methods and experimental validation.

Novel GαGTP Sensors Reveal Endogenous and Subcellular G Protein Signaling Dynamics

This paper introduces novel GαGTP sensors to measure endogenous G protein signaling dynamics, revealing subtype-dependent dissociation and subcellular regulation.

Intracellular targeting of a light-activated GPCR elicits spatially selective signalling

This study uses an optogenetic platform to activate a GPCR at different intracellular membranes, showing location-dependent transcriptional responses.

Designing Rigid Protein Fiducials to Visualize GPCR Conformational States

The paper designs rigid protein fiducials using generative design and deep learning to enable cryoEM visualization of GPCR conformational states, validated with four GPCR inactive structures.

HYALINE: Geometric Deep Learning for Accurate Prediction of G Protein-Coupled Receptor Activation States from Structure

Hyaline predicts GPCR activation states from 3D structures using geometric deep learning, achieving high accuracy and outperforming sequence-only models.

Stabilization versus flexibility: detergent-dependent trade-offs in neurotensin receptor 1 GPCR ensembles

This study investigates how different detergents affect the stability and ligand binding of neurotensin receptor 1, revealing a trade-off between structural stabilization and conformational flexibility.

Mapping the Ligand-dependent Remodeling of the Conformational Entropy Landscape in Neurotensin Receptor 1 by NMR-guided Molecular Simulations

This study uses NMR and MD simulations to analyze conformational entropy changes in GPCRs, showing how dynamic fluctuations influence allosteric signaling and receptor function.

The isolated Stachel peptide of the adhesion G protein-coupled receptor GPR126 is intrinsically disordered

The study shows the ADGRG6/GPR126 Stachel peptide is intrinsically disordered in solution, with limited helical conformations detected by biophysical experiments.

Sequence constraints predispose Class D GPCRs to follow an atypical activation mechanism

This study identifies sequence constraints that predispose Class D GPCRs to an atypical activation mechanism involving TM7 displacement and TM6 inward movement.

An engineered nanobody inhibitor for molecular-to-circuit control of opioid receptor function

This paper develops an engineered nanobody inhibitor to control opioid receptor function with subcellular precision and demonstrates its effectiveness in vivo.

μ-Opioid Receptor Superagonists Engage Sodium-Bound Receptor States

This paper investigates how superagonists at the μ-opioid receptor are less sensitive to Na+ ions compared to standard agonists, suggesting a conformational induction mechanism.

Atypical GPCR Activation Resolved by Nanobody Engineering

This study reveals an unconventional activation mechanism of the atypical GPCR ACKR3 using engineered nanobodies and cryo-EM, showing that extracellular pocket volume changes, not microswitch conformational shifts, drive receptor activity.

Human class B1 GPCR modulation by plasma membrane lipids

The paper uses molecular dynamics simulations and FRET assays to study lipid interactions with class B1 GPCRs, revealing state-dependent and conserved lipid binding patterns.

Distinct Membrane Binding Properties of the Two Non-visual Arrestins

This study compares the membrane-binding properties of arrestin-2 and arrestin-3 using biophysical and cell-based methods, revealing distinct lipid interaction mechanisms and activation dynamics.

All roads lead to Rome: Emergence of Mechanistic Divergence Shapes Activation of Class B1 G-Protein Coupled Receptors

This study uses MD simulations to show that Class B1 GPCRs share a common activation mechanism involving an intermediate state with outward movement of helix 6, but exhibit clade-specific residue-level differences.

A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function

This paper describes a pepducin derived from NTS1 that acts as a biased allosteric modulator, preferentially activating G proteins over β-arrestin and inhibiting receptor internalization.

Angiotensin receptor conformations stabilized by biased ligands differentially modulate β-arrestin interactions

The paper shows that biased ligands of the AT1R receptor stabilize different conformations that differentially modulate β-arrestin interactions, affecting signaling and desensitization.

Visualizing the Dominant GPCR Coupling of Pathogenic Gαo Mutants in GNAO1-Related Disorders

This study uses a split-YFP BiFC assay to show that severe GNAO1 mutations impair GPCR disengagement, while milder mutants show near-normal receptor internalization.

The role of intrinsically disordered domains in regulating G protein coupled receptor signaling

This study uses single-molecule imaging to show how agonist-specific dynamics in structured and disordered regions of the 2AAR regulate signaling and function.

Mechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor

This study uses Pep-GaMD simulations to reveal how a tethered agonist transitions from a β-strand to a U-shaped helical configuration upon binding to ADGRD1.

Non-Equilibrium Snapshots of Ligand Efficacy at the μ-Opioid Receptor

The paper uses cryo-EM to capture non-equilibrium states of the μ-opioid receptor bound to different ligands, revealing ligand-dependent conformational dynamics and G-protein activation differences.

Dissecting GPCR Selectivity: A complex interplay of various intracellular motifs determines G-protein binding and activation

This study investigates how intracellular motifs in Muscarinic receptors influence G-protein binding and activation, showing that selectivity arises from complex interactions rather than single motifs.