August 2022 A NanoBRET-Based H 3 R Conformational Biosensor to Study Real-Time H 3 Receptor Pharmacology in Cell Membranes and Living Cells "Conformational biosensors to monitor the activation state of G protein-coupled We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor Hence, the H3R conformational biosensor in membranes might be a ready-to-use, high-throughput alternative

September 2022 Interacting binding insights and conformational consequences of the differential activity Namely, CBD has been suggested to directly trigger receptor’s activation, stabilize CB1 inactive conformations From microsecond-length unbiased molecular dynamics simulations, we found that the presence of the CBD ligand in the GPR55 receptor elicit conformational changes associated with antagonist-bound GPCRs. The all-atom MD simulations reveal that CBD induces conformational changes linked with agonist-bound

June 2022 "G protein-coupled receptors (GPCRs) represent a major therapeutic target class as they play a key role in many (patho-) physiological processes. GPCRs are divided into six classes based on amino acid sequence similarities, but only four of the classes (A, B, C, and F) are found in humans. GPCRs respond to a wide variety of signals that range in size from photons to proteins (Foord et al., 2005). GPCRs continue to be regarded as one of the most tractable classes of drug targets and are targeted by 30%–40% of current drugs (Hauser et al., 2017), with annual sales of GPCR-targeting drugs in 2018 accounting for >114 billion USD. In 2019, 5 out of 20 first-in-class approved therapeutic agents targeted GPCRs. Despite this high number of GPCR targeted drugs, only a small portion (∼110) of the human GPCRome (consisting of approximately 850 GPCRs) has been successfully drugged, and obtaining highly potent and selective small molecules remains a challenge for the remainder." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling regulatory processes for over 800 different G protein-coupled receptors (GPCRs) by adopting specific conformations Furthermore, the utilisation of advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational Moreover, we assess β-arrestin conformational changes that are induced specifically by proximal and distal Here, we show differences between conformational changes that are induced by P-R* or R* receptor states

September 2022 Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1 In this work we present the study of the CX3CR1 receptor employing extensive atomistic Molecular Dynamics (MD) simulations with the aim to characterize the conformational ensemble of the receptor in the presence We analyzed the receptor conformational changes and described interactions within its key regions and

October 2022 "G protein-coupled receptors (GPCRs) are important drug targets characterized by a canonical seven transmembrane (TM) helix architecture. Recent advances in X-ray crystallography and cryo-EM have resulted in a wealth of GPCR structures that have been used in drug design and formed the basis for mechanistic activation hypotheses. Here, ensemble refinement (ER) of crystallographic structures is applied to explore the impact of binding of agonists and antagonist/inverse agonists to selected structures of cannabinoid receptor 1 (CB1R), β2 adrenergic receptor (β2 AR) and A2A adenosine receptor (A2A AR). " Read more at the source #DrGPCR #GPCR #IndustryNews

Capturing the dynamics of GPCR activation has always been a challenge because G protein activation in The captured structures reveal a dynamic of conformational changes initiated by the binding of an agonist This detailed process provided by the cryo-EM study offers a clear view of these dynamic states, from With this high-resolution, dynamic view of GPCR activation, scientists can better tackle diseases by This approach is valuable for understanding the dynamics of other complex signaling pathways and molecular

highlight includes congrats to Omolade Otun , Chris de Graaf , Cherine Bechara , et al. for their work on Conformational dynamics underlying atypical chemokine receptor 3 activation   Michael Trogdon , J Silvio Gutkind ’s dive into the   Classified GPCR News  from July 15th to 21st, 2024 GPCR Activation and Signaling Conformational dynamics underlying atypical chemokine receptor 3 activation RhoA-mediated G12-G13 signaling maintains guidance  Crinetics Pharmaceuticals to Report Second Quarter 2024 Financial Results on August 8, 2024 Dynamic

Fine-tuning GPCR signaling: conformational dynamics and intracellular responses GPCR signaling is a complex Consequently, understanding dynamic interactions between effectors during trafficking becomes crucial However, both methods struggle with flexible or dynamic regions. Other techniques include nuclear magnetic resonance (NMR) spectroscopy for conformational dynamics analysis The combination of these diverse methods contributes to a holistic understanding of the intricate dynamics

Molecular dynamics (MD) simulations on a 1-μs time scale and metadynamics-enhanced conformational sampling The endogenous peptide ligand endomorphin-1 (EM-1) underwent almost no significant conformational changes We verified the role of some key residues in the dynamic recognition of naloxone and morphine and identified directly into an agonist of MOR, and I322A also significantly attenuated the potency of MOR on EM-1, confirming This finding reveals a dynamic mechanism for the response of MOR to different ligands and provides a

We have carried out MARTINI coarse-grained molecular dynamics simulations of SMO in POPC and in ciliary , and to gain molecular-level insights into the role of the primary cilia in shaping the functional dynamics Further detailed analysis of the dynamics of the TMD reveals the movements of TM5, TM6, and TM7, linked with the helix8, which are possibly involved in shaping the conformational disposition of the ICD.

September 2022 Dynamics of tumor-associated macrophages in a quantitative systems pharmacology model ) serve as major contributors to the immuno-suppressive tumor microenvironment, we incorporated the dynamics

October 2022 Cholesterol-Dependent Dynamics of the Serotonin1A Receptor Utilizing Single Particle Tracking To explore the role of cholesterol in lateral dynamics of GPCRs, we utilized single particle tracking

of the actin cytoskeleton upon modulation of membrane cholesterol and its consequences on membrane dynamics In this work, we explore the effect of reorganization of the actin cytoskeleton on membrane dynamics Specifically, we explore the role of actin cytoskeleton in regulating the dynamics of the serotonin1A For this, we analyzed the lateral dynamics of the serotonin1A receptor in cholesterol-depleted cells Notably, our results show that statin-induced dynamic confinement could be reversed by destabilization

interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics Here, we have implemented an optimized approach of combining the data derived from steered molecular dynamics

To explore the role of cholesterol in lateral dynamics of GPCRs, we utilized single particle tracking

GPCR Volunteers Join our dynamic team as a volunteer! You'll share your contributor articles with the community, stay updated with GPCR literature, join a dynamic Dynamics of the Vesicle-Reconstituted β2 Adrenergic Receptor at the Single-Molecule Level Pharmacological precision therapeutics in psychiatric disorders Discovery of a Photoaffinity Probe that Captures the Active Conformation Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics

Structural and Molecular Insights into GPCR Function Sub-millisecond conformational dynamics of the A2A SLAS Europe 2023 Conference and Exhibition. (May 22 - 26, 2023) 2nd LEAPS Meets Life Sciences Conference. The Illuminating the Understudied Druggable Proteome Conference.

September 2022 β2-Adrenergic Receptor Expression and Intracellular Signaling in B Cells Are Highly Dynamic

GPCR Target Gunnar Schulte, Lukas Grätz, Pawel Kozielewicz, et al. for their study on Frizzleds act as dynamic origins of bitter taste receptors in jawed vertebrates Methods & Updates in GPCR Research Exploring GPCR conformational dynamics using single-molecule fluorescence Droplet-based microfluidic platform for detecting agonistic protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery Frizzleds act as dynamic 20th Annual PEGS Boston Summit May 16 - 19, 2024 | ASPET 2024 May 27 - 29, 2024 | SLAS Europe 2024 Conference

Biased agonists differentially modulate the receptor conformation ensembles in Angiotensin II type 1 Structural and Molecular Insights into GPCR Function Global insights into the fine tuning of human A2AAR conformational dynamics in a ternary complex with an engineered G protein viewed by NMR. The Illuminating the Understudied Druggable Proteome Conference.

Register today for the GPCR Drug Discovery Conference and save $200 with discount code “ DRGPCR24 ”. Cell swelling enhances ligand-driven β-adrenergic signaling Roles of the gate loop in β-arrestin-1 conformational dynamics and phosphorylated receptor interaction Early Events in β2AR Dimer Dynamics Mediated by Activation-Related

probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations "The δ-opioid receptor (DOR) is a critical pharmaceutical target this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular dynamic Major conformational differences were located on transmembrane (TM) 5 and 6, as well as intracellular Compared to naltrindole, ADL5859 exhibited high conformational flexibility and strong interaction with

Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded opsin indicated that phospholipid headgroups traverse a dynamically revealed hydrophilic groove between inhibits phospholipid scrambling by occupying the TM6/7 interface and stabilizing the closed groove conformation

Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97-Go complex The conformational landscapes analyzed by Markov state models revealed that the overall conformation

summarizes different PTMs in GPCR internalization and analyzes their significance in GPCR internalization dynamics

The computational modeling and the 1.5-μs molecular dynamics data presented in the current study are