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Burger , Arthur Christopoulos , David M. Thal , et al., for their groundbreaking work on Positive allosteric modulation of a GPCR ternary complex

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses - termed bias - potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct. Read full article

Terry’s Corner: Why Binding Kinetics Matter More Than Affinity In drug discovery today, time wasted is interpret kinetic binding experiments and recognize when a drug’s rate of onset and offset matter more than

When complexity grows faster than strategy, biotech companies begin to fall apart quietly. 👉 This article When complexity grows faster than clarity 👉 Early-stage biotech is complex by default. The problem begins when they expand faster than the company’s ability to make clear decisions. More experiments feel safer than fewer deliberate ones.   Scientists trust leadership because decisions are grounded in logic rather than mood.

I’m honored to be chairing a session  in this track — with none other than Terry Kenakin  on the speaker Hearing Terry speak is more than an academic experience — it’s like being handed a new set of tools to

Exploring the kinetic factors that enhance in vivo efficacy beyond traditional potency metrics, as presented by Dr. GPCR. Hey GPCR Fans, This week's breakthroughs are crucial for staying ahead in the rapidly evolving landscape of GPCR research and drug discovery. Dr. Terry Kenakin's insights on target residence time can reshape how you evaluate and advance lead compounds, potentially saving your team from costly late-stage failures. That's exactly what Dr. GPCR delivers every week: practical tools and critical intelligence to elevate your science and sharpen your decisions. Breakthroughs this week: Novo Nordisk cuts Ozempic® cost; Nxera launches obesity pipeline; Superluminal–Lilly cardiometabolic partnership; New GPCR allosteric sites; GPCR signaling potentiation by ATP and sugars. 🔍 This Week in Dr. GPCR Premium: Sneak Peek Get a glimpse of the in-depth intelligence available exclusively to our Premium Members this week: Industry insights:  Discover the latest strategic moves in the pharmaceutical sector, from new pipelines targeting obesity to significant collaborations in cardiometabolic disease, and gain insights into novel approaches in neurodegeneration and antibody therapeutics. Upcoming events:  Stay informed about key global conferences and symposia focusing on GPCRs, neuropharmacology, drug discovery, and biophysics, ensuring you don't miss crucial networking and learning opportunities. Career opportunities:  Explore a selection of high-level job openings in high-throughput screening, research, biologics development, clinical operations, and biostatistics within leading organizations. Must-read publications:  Stay updated on cutting-edge research, including the potentiation of GPCR signaling by ATP and sugar monophosphates and the identification of a novel allosteric site on the vasopressin V2 receptor. Terry's Corner - Unlock the Power of Target Residence Time in Your GPCR Drug Discovery Pipeline Gain a critical edge by understanding the in vivo efficacy drivers overlooked by traditional potency metrics. Are your promising in vitro results failing to translate into real-world clinical success? Dr. Terry Kenakin’s latest insights delve into target residence time, revealing why kinetic persistence often trumps binding affinity for in vivo efficacy. Discover how factors like restricted tissue diffusion and receptor density can dramatically alter drug action, potentially unlocking the true potential of your lead compounds. Problem Solved:  Eliminate the blind spots in your drug evaluation process, moving beyond simple potency measures to understand the dynamic interactions that govern in vivo effectiveness. Competitive Edge:  Identify high-value compounds that might be missed by traditional screening methods, gaining a first-mover advantage in developing more effective therapeutics. Threat Avoided:  Prevent costly late-stage failures by incorporating kinetic modeling early in your pipeline, ensuring your candidates have the persistence needed for clinical impact. ➡️  Premium Members get 50%+ discount when they join Terry’s Corner. Access this week’s key insight ➤ Dr GPCR Podcast – Decoding the Deadly Duo: Xylazine, Fentanyl, and Respiratory Depression Understand the synergistic mechanisms driving the escalating opioid crisis and the crucial role of GPCR pharmacology. The opioid crisis is evolving with the dangerous combination of fentanyl and the veterinary sedative xylazine. This week’s featured podcast episode with Catherine Demery explores the distinct yet lethal mechanisms by which these drugs impair respiration. Learn how fentanyl slows inhalation via opioid receptors, while xylazine prolongs exhalation through alpha-2 adrenergic receptors, creating a synergistic effect that drives overdose deaths. Catherine’s research, blending GPCR signaling studies with public health data, offers critical insights into this urgent crisis. Problem Solved:  Gain a deeper understanding of the pharmacological underpinnings of opioid overdose, informing the development of more effective intervention strategies. Competitive Edge:  Stay informed on emerging public health threats and the scientific research aimed at addressing them, positioning your work at the forefront of critical biomedical challenges. Threat Avoided:  Recognize the growing prevalence and dangers of xylazine-laced opioids, enabling you to contribute to solutions and understand the broader impact on public health. Listen now to understand how two mechanisms intersect—and why pharmacologists are critical in addressing this crisis ➤ Call for Papers – GPCRs: Signal Transduction Volume II With over 21,000 views  and 7,785 downloads  from Volume I, the Signal Transduction  Research Topic is back. Volume II invites experts to deepen our collective understanding of GPCR pathways in health and disease. Manuscript summary deadline: 24 September 2025 . Final submissions: 12 January 2026 . Why contribute: Join a global, like-minded GPCR community. Shape the next generation of cellular biochemistry research. Amplify your work with high-impact visibility. Submit your paper today to secure your work in Volume II ➤ Why Dr. GPCR Premium Membership Gives You an Edge Every week, Premium delivers noise-free intelligence : expert-led courses, classified industry insights, curated events, exclusive job opportunities, and insider commentary. Designed for GPCR scientists and translational teams, Premium keeps you informed on the science, careers, and business moves shaping drug discovery. Unlike fragmented feeds and endless searches, Premium is structured to help you move faster, smarter, and with greater clarity. FAQ: Premium Membership 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, exclusive on-demand expert lectures, and member-only discounts. 🔹 Who is it for? GPCR scientists, translational pharmacologists, biotech discovery teams, and decision-makers who need career-relevant intelligence to stay ahead. 🔹 Why now? 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GPCR Summit 2022 is less than a month away!

August 2022 "Opioid receptors (ORs) represent one of the most significant groups of G-protein coupled receptor (GPCR) drug targets and also act as prototypical models for GPCR function. In a constant effort to develop drugs with less side effects, and tools to explore the ORs nature and function, various (poly)pharmacological ligand design approaches have been performed. That is, besides classical ligands, a great number of bivalent ligands (i. e. aiming on two distinct OR subtypes), univalent heteromer-selective ligands and bitopic and allosteric ligands have been synthesized for the ORs. The scope of our review is to present the most important of the aforementioned ligands, highlight their properties and exhibit the current state-of-the-art pallet of promising drug candidates or useful molecular tools for the ORs." Read more at the source #DrGPCR #GPCR #IndustryNews

M.; Compton, D. R.; Martin, B. R.; Abood, M. E. , M. C.; Westphal, M. V.; Mostinski, Y.; Mach, L.; Wasinska-Kalwa, M.; Weise, M.; Hoare, B. .; Maccarrone, M.; Veprintsev, D. B.; Carreira, E. M.; Grether, U.; Nazaré, M. F.; Nicolotti, O.; Perrone, M. G.; Brea, J.; Loza, M. I.; Infantino, V.; Abate, C.; Contino, M.

and chemistry pulled him into the world of GLP-1R, pancreatic β-cells, and the biological questions David The call from David — the glowing islet — created a pivot the team couldn’t ignore. This was more than data. It was ignition. He learned tissue complexity from David; David picked up the quirks of acetonitrile. David Hodson

M., & Fields, S. (2014). Deep mutational scanning: a new style of protein science. M., Marti-Solano, M., Sandhu, M., Kobilka, B. K., Bouvier, M., & Babu, M. M. (2023). Kosar, M., Sarott, R. C., Sykes, D. A., Viray, A. E., Vitale, R. M., Tomašević, N., ... & Carreira, E. M. (2024). M., Christopoulos, A., & May, L. T. (2016).

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E., Healy, M. D., & Collins, B. M. (2019). , Gonçalves-Monteiro, S., Vieira-Rocha, M. M., & Lefkowitz, R. J. (2003). B., Conti, M., & von Zastrow, M. (2017). M., & Murray, F. (2018).

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David Hodson needed molecules that were only one synthetic step beyond what JB was already making. When David later shared early data — including a moment where he realized he could image an entire islet David brought deep experience in islet biology, calcium imaging, and tissue physiology. David picked up unexpected chemistry insights — including a well-loved lesson involving acetonitrile David Hodson

G., Frielle, T., Bolanowski, M. A., Bennett, C. D., Rands, E., Diehl, R. E., Mumford, R. S., Caron, M. G., Lefkowitz, R. J., & Strader, C. D. (1986). Nature, 321(6065), 75–79. https://doi.org/10.1038/321075a0 Fredriksson, R., Lagerström, M. M., Pérez-Hernández, G., Batebi, H., Gao, Y., Eskici, G., Seven, A. B., Panova, O., Hilger, D., Casiraghi, M., He, F., Maul, L., Gmeiner, P., Kobilka, B.

Watch Episode #177 The Experiment That Was Never Meant to Succeed When David Hodson’s lab teamed up with therapeutic benefit Where not  to target to avoid adverse effects Why GPCR Imaging Tools Matter More Than David Hodson

As JB puts it, the cost of not asking is much higher than the cost of momentary discomfort. In his collaboration with David Hodson, every major leap—from early ligand design to GPCR visualization This mindset shapes careers far more than publications alone. David Hodson

This Week’s Highlights: G protein-coupled receptor (GPCR) pharmacogenomics Miles D Thompson , David Reiner-Link , Alessandro Berghella , Brinda K Rana , G Enrico Rovati , Valerie Capra , Caroline M Gorvin Abigail Alwin , Campbell Krusemark , Ezequiel Marron Fernandez de Velasco , Steven H Olson , Lauren M

of GPCR activation has always been a challenge because G protein activation in cells occurs in less than A recent breakthrough study published in Nature by Makaía M. Papasergi-Scott, M. M. et al. Time-resolved cryo-EM of G-protein activation by a GPCR.

role in disease pathology and highlight allosteric sites that might be more amenable to drug targeting than M. (2011). Deep mutational scanning: assessing protein function on a massive scale. M., Stephany, J. J., & Fields, S. (2014). Nature Protocols , 9 (9), 2267–2284. https://doi.org/10.1038/nprot.2014.153 Howard, M. M., Trinidad, D. D., English, J. G., Coyote-Maestas, W., & Aashish Manglik. (2024).

Butlen-Ducuing F, Pétavy F, Guizzaro L, Zienowicz M, Salmonson T, Haas M, et al. Wouters OJ, McKee M, Luyten J. Schlander M, Hernandez-Villafuerte K, Cheng CY, Mestre-Ferrandiz J, Baumann M. Yamaguchi S, Kaneko M, Narukawa M. Persechino M, Hedderich JB, Kolb P, Hilger D.

M., Medel-Lacruz, B., Baidya, M., Makarova, M., Mistry, R., Goulding, J., Drube, J., Hoffmann, C., Owen M., Shukla, A. K., Selent, J., Hill, S. J., & Calebiro, D. (2023). M., Kawakami, K., Masureel, M., Maeda, S., Garcia, K. C., von Zastrow, M., Inoue, A., & Kobilka, B. I., & von Zastrow, M. (2001).

50% displacement threshold and progressed to seven-point concentration–response assays (10⁻¹⁰ to 10⁻⁶ M) Table reporting the % of displacement measured at 1 µ M and the corresponding Ki for those showing a % higher than 50%. Hoechst-stained nuclei (blue) across increasing concentrations of AAN396, AAN397 and AAN405 (10⁻¹⁰ to 10⁻⁶ M) validation in intact cells, the approach provides a richer picture of ligand–receptor interactions than

K., Odongo, S., Radwanska, M., & Magez, S. (2023). M., Thian, F. S., Kobilka, T. S., Schnapp, A., Konetzki, I., Sunahara, R. K., Gellman, S. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. M., Christopoulos, A., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H.

The donors used in this technique have longer half-lives  than other fluorophores (between 300μs–1 ms Terbium, a second-generation donor, is brighter than Europium (10-20 times), which increases sensitivity The donor lanthanum fluorophores are more stable than regular fluorophores and quite resistant to photobleaching Source: Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M. References Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M.

References Barbazán J, Majellaro M, Martínez AL, Brea JM, Sotelo E, Abal M. Soave M, Briddon SJ, Hill SJ, Stoddart LA.

M. Aragay et al. 1998). Removal of G proteins by using CRISPR KO of Gαi (Gαi KO) or KO of all Gα subtypes (Gα_all KO) (M. constitutively internalize through clathrin-coated pits independently of phosphorylation and β-arrestin (M. M. Paing et al. 2022; J. L. Sapmaz et al. 2019, M. N. J. Seaman 2012).

References Fessl T, Majellaro M, Bondar A. Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M.

Thanks to the unique linker structure we obtain, which can be divided into three differentiated parts   (5) Meldal, M.; Tornøe, C. W. Cu-Catalyzed Azide−Alkyne Cycloaddition. Chem.