Receptor Mechanisms and Signaling

Analytical methodology for unveiling the physical effect of detergents on the function of full-length membrane proteins using a single-molecule tracking system

This paper develops a single-molecule tracking method to assess ligand-binding ability of full-length β2AR without purification, revealing how detergent microenvironments affect protein stability and function.

Distal conformational steering by N-terminal pyroglutamylation enables subtype-selective GPCR activation across Aplysia PRXamide and human Neuromedin U signaling

The paper shows how N-terminal pyroglutamylation (pQ) biases GPCR activation by altering ligand conformation and receptor pocket mechanics, enabling subtype-selective signaling in both Aplysia and human systems.

A highly dynamic active state for transducin-bound phosphodiesterase-6 in vertebrate phototransduction

This paper uses biophysical techniques to show that GT* binding to PDE6 induces a dynamic active state, revealing a previously unobserved conformation associated with catalysis.

Ehrlich occupancy time: Beyond koff to a complete residence time framework

The paper introduces a new framework for calculating drug-target occupancy time that incorporates association, dissociation, rebinding, and elimination rates, showing how these factors jointly influence in vivo efficacy.

Molecular principles for graded activation of dopamine D1 receptor

The paper defines the molecular mechanism of graded activation of the dopamine D1 receptor and shows how ligand efficacy is encoded through an activation pathway.

Ligand-Specified Signaling Efficacy Defined by Unique Transitions in G Protein Conformations

This study quantifies Gs protein conformational transitions in response to different ligands, revealing ligand-specific dynamics that determine GPCR signaling efficacy.

DeorphaNN: Virtual screening of GPCR peptide agonists using AlphaFold-predicted active-state complexes and deep learning embeddings

DeorphaNN identifies peptide agonists for GPCRs using AlphaFold structural predictions and deep learning embeddings, successfully uncovering agonists for two orphan receptors across species.

Chemokine receptor activity is differentially regulated by membrane cholesterol

This study shows cholesterol modulates chemokine receptor activity differently, affecting some receptors but not others, and distinguishes cholesterol from oxysterols in their effects.

β-arrestin recruitment facilitates a direct association with G proteins

This study shows that G proteins and β-arrestins can directly interact, with Gi family members differing in their association with β-arrestin, and this selectivity is located in the alpha helical domain of Gi.

Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules

The paper identifies and characterizes small molecule allosteric modulators of the AT1R, revealing their conformational mechanisms and effects on G protein and β-arrestin pathways.

Modulation of the agonist and antagonist activity of peptidic FPR1 ligands through N-terminal modifications: A structural and functional analysis

Cryo-EM structure of a single-chain β1-adrenoceptor - AmpC β-lactamase fusion protein

The paper presents the cryo-EM structure of a β1-adrenoceptor-AmpC β-lactamase fusion protein in the inactive state, revealing conformational dynamics and potential for GPCR structure elucidation.

Structural insights on the ligand selectivity of the mouse trace amine-associated receptor TAAR7e

This study investigates the molecular mechanisms of ligand selectivity in mTAAR7e using homology modeling, structure-activity analysis, and mutagenesis, revealing structural determinants for preference toward longer carbon chains and tertiary amines.

Adenylyl cyclases combinatorially integrate opposing dopamine receptor signals

The paper shows that adenylyl cyclases integrate opposing dopamine receptor signals in neurons, with AC isoform expression determining signal outcomes.

Crosstalk of noradrenergic Ca2+ and cAMP signaling in astrocytes of the murine olfactory bulb

The paper investigates the interaction between Ca2+ and cAMP signaling in mouse olfactory bulb astrocytes, showing how different adrenergic receptors modulate these pathways.

Dualsteric and dual-acting modulation of muscarinic receptors by antagonist KH-5

This study investigates KH-5's dualsteric and dual-acting modulation of muscarinic receptors, finding it acts as a dualsteric antagonist at M1 receptors and competitive antagonist at M2 receptors.

Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors

This study investigates how odorant receptors regulate selectivity and antagonism through allosteric gating mechanisms using simulations and experiments.

Cryo-EM Structures of Brain-Derived G Protein-Coupled Receptors

The paper uses cryo-EM to analyze endogenous mGluR2-containing receptor assemblies in mouse brain, revealing distinct structural states and complexes not previously observed in recombinant systems.

Coordinated subpocket engagement underlies nitazene potency at the μ-opioid receptor.

The paper identifies structural determinants of nitazene potency at the μ-opioid receptor using functional assays, quantum mechanics, and molecular dynamics simulations.

An adhesion GPCR regulates cell adhesion and mating in the closest living relatives of metazoans

This study identifies Cupidon, an adhesion GPCR in Salpingoeca rosetta, which regulates cell adhesion and mating by modulating proteolytic processing and localization during nutrient conditions.

Adenylyl cyclase 9: fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication

The paper examines the evolution of adenylyl cyclase 9 regulation in vertebrates, showing how teleost-specific whole-genome duplication led to sub-functionalization of adcy9 ohnologs.

Gβγ engages PLCβ3 at multiple sites to reorient and facilitate its activation

This study shows Gβγ enhances PLCβ3 activation by reorienting its catalytic site, working with Gq to increase PI(4,5)P2 hydrolysis and Ca2+ release.

Who's driving? Common evolutionary mechanism of activation of class A GPCRs

The paper identifies a common evolutionary mechanism for class A GPCR activation using coevolution and machine learning, validated through molecular dynamics simulations and ligand effect modeling.

Sulfo-DIBMA encapsulation uniquely preserves signalling-competent active states of class B1 GPCRs, CGRP and PTH1 receptors, in native-like nanodiscs

This paper shows that sulfo-DIBMA nanodiscs preserve active-state signaling of class B1 GPCRs better than other copolymers, enabling functional studies of these receptors.

Small-molecule modulation of Beta-arrestins

This study identifies small-molecule inhibitors of beta-arrestins and elucidates their mechanism, offering a framework for modulating GPCR signaling.

Structural and Dynamic Basis of TREM2--DAP12 Stabilization by Small-Molecule Agonist VG-3927

This study investigates how the small-molecule agonist VG-3927 stabilizes the TREM2-DAP12 complex by binding within a transmembrane cavity and altering its conformation.

Molecular mechanism of naturally-encoded signaling-bias at the complement anaphylatoxin receptors

This paper identifies naturally-encoded signaling bias at C5aR1 and C5aR2 receptors through structural and functional analyses, revealing molecular mechanisms underlying biased signaling in GPCRs.

A complete RXFP1-relaxin interaction model unlocks the design of potent mini-protein modulators

This study uses AI to model RXFP1-relaxin interactions and designs potent mini-protein modulators that act as agonists or antagonists.

Antagonists Perturb the MC2R MRAP Complex and Reshape Receptor Conformations

This study uses mass spectrometry to show how MRAP and antagonists affect MC2R conformations and dynamics.

Buprenorphine Restricts the Conformational Landscape of the μ-Opioid Receptor

This study uses simulations to show that buprenorphine restricts the conformational states of the μ-opioid receptor compared to endomorphin-1, affecting signaling bias and efficacy.