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initiate SMOOTHENED-PKA signaling in the Hedgehog cascade Elita Yuliantie , Arthur Christopoulos , Patrick M. Sexton , Denise Wootten , et al., for their work on Isoquinoline small molecule ligands are agonists

Molecular insights into G protein coupling specificity at a class A GPCR Jianjun Cao, Arthur Christopoulos, Patrick M. Sexton et al. for their job on Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP

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

Hi! We’re diving into May with serious momentum. This week brings sharp new insights into how minor changes in ligand structure can flip GPCR function, how ACKR3 modulates cardiac lymphatic repair, and how β-arrestins decode GPCR phosphorylation barcodes. Plus, check out the latest Dr. GPCR tools and key moves in the biotech world. Dr. GPCR Updates   We want your feedback - Help shape the future of Dr. GPCR.   Your voice matters. Every insight you share helps us build a smarter, more supportive GPCR community—together. Got a minute? Tell us what’s working and what’s missing .     Become a Dr. GPCR Ambassador - Share & refer with Dr. GPCR.   Help grow the GPCR community by joining the Dr. GPCR affiliate program. When someone signs up for a course, membership, or event through your referral link, you’ll receive a referral reward. It’s a simple way to share valuable resources and support the field—one connection at a time.   Join the Affiliate Program     Your Shortcut to Dr. GPCR University - A fast-reference guide for you!   The Dr. GPCR University Cheatsheet   is your quick-start guide to everything we offer—no downloads, no digging. Filter by topic, format, or access level to find exactly what you need to boost your GPCR knowledge.   Explore the Cheatsheet GPCR Publication Highlights   — Minimal Structural Variation of GPR84 Full Agonist Causes Functional Switch to Inverse Agonism   — ACKR3 Regulates the Cardiac Lymphatic Response After Ischemic Heart Injury.   — Phosphorylation “Barcodes” Tune β-arrestin Isoform Signaling via Allosteric Networks . Want the full breakdown? Explore this week’s research, tools, and biotech insights in one place. Collaboration is the catalyst—let’s redefine what’s possible in GPCR-driven therapeutics.    Best wishes, The Dr. GPCR Team

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

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). J., Sexton, P. M., Christopoulos, A., & May, L. T. (2016).

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

Vladimir Katanaev and Patrick Sexton. Continuing Study Addex Therapeutics in the 23rd BioEquity Europe Conference Simon Bekker-Jensen and Mette M

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. B., Mehrotra, E., Patrick Rockefeller Grimes, Zahm, A. M., Trinidad, D. D., English, J.

., 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.

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. van der Westhuizen ET, Valant C, Sexton PM, Christopoulos A.

M., Marti-Solano, M., Sandhu, M., Kobilka, B. K., Bouvier, M., & Babu, M. M. (2023). Howard, M. K., Hoppe, N., Huang, X. P., Macdonald, C. B., Mehrota, E., Grimes, P.

., Vieira-Rocha, M. S., Vojtek, M., Sousa, J. B., & Diniz, C. (2021). E., Healy, M. D., & Collins, B. M. (2019). M., & Lefkowitz, R. J. (2003). B., Conti, M., & von Zastrow, M. (2017). M., & Murray, F. (2018).

This Week’s Highlights: Celebrating Excellence:   Patrick Sexton  and Arthur Christopoulos  Named Among

., Bolanowski, M. A., Bennett, C. D., Rands, E., Diehl, R. E., Mumford, R. A., Slater, E. 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. ., Casiraghi, M., He, F., Maul, L., Gmeiner, P., Kobilka, B. K., Hildebrand, P.

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).

Patrick Sexton, and Matthew Belousoff et al. for their work on Lipid-Dependent Activation of the Orphan

A recent breakthrough study published in Nature by Makaía M. Twenty transition structures generated from overlapping particle subsets along this pathway provide a Papasergi-Scott, M. M. et al. Time-resolved cryo-EM of G-protein activation by a GPCR.

The fission yeast Schizosaccharomyces pombe has two mating types, Plus (P) and Minus (M). investigated the stringency of the two GPCRs, Mam2 and Map3, for their respective pheromones, P-factor and M-factor acid residues of Map3, F214 and F215, are key residues important for discrimination of closely related M-factors

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).

M. et al. 2018; Manglik, A. et al. 2012). the formation of dimers and alter their function by destroying the interface between two receptors (M. structure of CB1R–5HT2AR heterodimers, preventing cognitive impairment while preserving analgesia in vivo (M.

H. 2020, Casiraghi, M. et al. 2019), double electron-electron resonance (DEER) spectroscopy for high-resolution M. et al. 2019), and hydrogen-deuterium exchange (HDX) mass spectrometry for time-dependent conformational M. et al. 1999), while dual knockout is lethal (Schmid, C. L., & Bohn, L. M. 2009).

Franziska M Heydenreich, Michel Bouvier, Brian Kobilka, M Madan Babu, and their team's work on Molecular

David Reiner-Link , Alessandro Berghella , Brinda K Rana , G Enrico Rovati , Valerie Capra , Caroline M Abigail Alwin , Campbell Krusemark , Ezequiel Marron Fernandez de Velasco , Steven H Olson , Lauren M

M, et al. 2023).

., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024).

presents a significant challenge when it comes to detecting and confirming allosteric behaviors (Keov, Sexton

Bouvier, M., Oligomerization of G-protein-coupled transmitter receptors.