Receptor Mechanisms and Signaling

Slow Dissociation of Nitazenes from the μ-Opioid Receptor Underlies the Challenge of Overdose Reversal

The paper investigates the slow dissociation of nitazenes from the μ-opioid receptor, showing it contributes to overdose reversal challenges and provides structural insights into the mechanism.

Integrative AlphaFold Modeling, Fragment Mapping, and Microsecond Molecular Dynamics Reveal Ligand-Specific Structural Plasticity at the Human Urotensin II Receptor

This study uses computational methods to analyze how different peptide ligands interact with the human urotensin II receptor, revealing structural differences in receptor activation.

A Rapid and Universal Pipeline for High-Resolution GPCR Structure Determination through In Silico Construct Optimization and de novo Protein Design

This paper introduces a pipeline combining AI-assisted construct screening and de novo protein design to rapidly determine high-resolution GPCR structures, validated on multiple receptors.

Quantitative Deciphering of Mammalian Histamine Receptors through Mathematical Genomics

This study analyzes mammalian histamine receptor sequences to identify evolutionary patterns and structural constraints across species.

Dynamic Monomer-Dimer Transition in Ligand-induced Apelin Receptor Activation

This study presents cryo-EM structures of the apelin receptor in various oligomeric states to elucidate the dynamic monomer-dimer transition and its role in signaling.

Unconventional Interplay Between GPCRs and RTKs Signaling Pathways Through SH2 Domain-Containing Proteins

This study identifies a novel mechanism where Gq/11 and G12/13 activation causes SH2 domain-containing proteins to translocate from the plasma membrane to the nucleus, reducing RTK signaling activity.

Structural Basis of M1 Muscarinic and H3 Histamine Receptor Inhibition in OPC Differentiation

The paper identifies M1 muscarinic and H3 histamine receptors as targets for OPC differentiation and analyzes their ligand interactions using computational methods.

Steroid-based Tide Quencher 1 probes enable real-time mapping of novel non-canonical cholesterol sites on the M1 muscarinic receptor

This paper introduces TQ1 probes to map non-canonical cholesterol-binding sites on the M1 muscarinic receptor, showing improved quenching and binding specificity compared to Dabcyl.

Decoding the Structural and Functional Impact of the Leukaemia-Associated A338V Mutation in GPR183

This study examines how the A338V mutation in GPR183 affects receptor function, showing preserved G protein activation but impaired GRK2 and β-arrestin2 recruitment.

Sodium Ions Regulate GPCR Activation by Remodeling Allosteric Coupling Networks and Hydration Patterns

This study shows sodium ions regulate GPCR activation by altering allosteric coupling networks and hydration patterns in the dopamine D2 receptor.

Functional diversity of GPCR-Gustducin complexes controls signaling output and suppresses alternative pathways

The paper develops biosensors to study GPCR-Gustducin interactions and finds that some non-taste GPCRs suppress signaling by forming unproductive complexes that block alternative pathways.

Activation mechanism of class A GPCRs: machine learninganalysis of experimental structural databases

This study uses machine learning to analyze structural data of class A GPCRs, revealing that ligand binding follows conformational selection while G protein binding stabilizes the active state.

Parallel CRISPR screens reveal pathways controlling the cell surface levels of the attractant receptor FPR1

This study identifies regulators of FPR1 surface expression and internalization using CRISPR screens, revealing multiple pathways and previously unknown factors involved in receptor trafficking.

The importance of M1 muscarinic receptor phosphorylation in learning and memory

This study shows that M1 receptor phosphorylation is critical for contextual memory but not cued memory, and biased Gq signaling alone is insufficient for restoring contextual memory.

Location-biased β-arrestin conformations direct GPCR signaling

This study shows that β-arrestin conformations vary by subcellular location and influence ERK activation differently in response to agonists.

Investigator-blind discovery of structural elements controlling GPCR function

The paper develops an investigator-blind analysis pipeline to identify structural elements controlling GPCR function using molecular dynamics simulations and finds known microswitches and two potential new motifs.

GPCRs as Targets for Human Brain Modulation: A Multi-omic Atlas of Cell-Type Specific Expression

This study presents an atlas of orphan GPCR expression across the human brain for translational targeting.

Structural insights into human recoverin

This study provides structural insights into human recoverin, revealing its unique calcium and zinc interactions compared to bovine recoverin.

Adaptive receptor expression and the emergence of disease as loss of signaling homeostasis

The paper models adaptive receptor expression as a compensatory mechanism and finds it robust to oscillatory perturbations but not chronic stress, suggesting disease arises from exceeding compensatory limits.

Angiotensin 1-7 Modulates the Dynamics and Activation of the Proto-oncogene Mas Receptor

This study uses molecular dynamics simulations to show Ang 1-7 stabilizes the inactive conformation of MasR and induces limited activation through non-canonical micro-switch dynamics.

Computed atlas of the human GPCR-G protein signaling complexes

This study predicts 3D structures of human GPCR-G protein complexes using AlphaFold3 and uses machine learning to predict coupling potency, revealing new signaling mechanisms and coupling preferences across GPCR subtypes.

ABEL-FRET bridges the timescale gap in single-molecule measurements of the structural dynamics in the A2A adenosine receptor

This study uses ABEL-FRET to measure structural dynamics of A2A adenosine receptors across timescales, showing agonists shift receptor states and accelerate conformational exchange.

Structural insights into the inactive state of the adhesion GPCR ADGRV1

This study presents the cryo-EM structure of inactive ADGRV1 and shows it has weak constitutive activation and an alternative activation mechanism distinct from other aGPCRs.

Xylazine's k-opioid agonist activity is not shared with other FDA-approved alpha2-adrenergic agonists

The paper investigates whether other FDA-approved alpha2-adrenergic agonists share xylazine's kappa opioid agonist activity and finds they do not, but have distinct GPCR activity patterns.

A Transferable and Robust Computational Framework for Class A GPCR Activation Free Energies

This paper introduces a computational framework to calculate activation free energies for class A GPCRs, showing agreement with previous methods and providing new insights for the μ-opioid receptor.

Direct tensile force activates Adgrl3 in a tethered agonist-dependent manner

The paper shows that direct tensile force on Adgrl3's N-terminus activates G protein recruitment in living cells, requiring a functional tethered agonist and force-driven conformational changes.

Antagonist binding actively disrupts interleukin-1 receptor dynamics to block co-receptor recruitment

This study shows antagonist binding disrupts IL1R1 dynamics to block co-receptor recruitment, contrasting with agonist-induced stabilization of signaling conformations.

Signaling bias of the protease-activated receptor-1 is dictated by distinct GRK5 and β-arrestin-2 determinants

This study identifies the molecular mechanisms underlying signaling bias in PAR1, showing distinct roles of GRK5 and β-arrestin-2 in thrombin- and APC-induced responses.

Local GPCR density tips the balance of μ-opioid receptor trafficking

This study shows that increasing μ-opioid receptor density promotes trafficking via GRK2/3 and β-arrestin interactions, while class B GPCRs block trafficking by sequestering β-arrestin.

A conserved hydrophobic interaction governs GPCR-transducer association

The paper identifies a conserved hydrophobic interaction that mediates competition between GPCR transducers and regulators.