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Kathleen M Caron and her team studied the GPER/GPR30 complex with β1-adrenergic receptor and AKAP5 in

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

spatial availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical Although less characterized, canonical CKRs have also been shown to not only directly regulate migration M, et al. 2023).

December 2021 OMass Therapeutics's founder, Carol Robinson, has been awarded the prestigious Louis-Jeantet Benjamin Franklin Medal in Chemistry from The Franklin Institute "Huge congratulations to our founder, Carol

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.

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.

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).

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).

Kathleen Caron. Check out the weekly Classified GPCR News from October 23rd to 29th, 2023.

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. Slosky LM, Caron MG, Barak LS. Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.

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.

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).

of titratable residues spans from the extracellular surface to the transmembrane area, linking with canonical 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).

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M.; Bucolo, C.; Platania, C. B. M.; Salomone, S.; Drago, F. W.; Högl, B.; Bainbridge, J.; Buchfuhrer, M.; Hadjigeorgiou, G.; Inoue, Y.; Manconi, M.; Oertel, W.; -J.; Kopanchuk, S.; Laasfeld, T.; Weinhart, M.; Schollmeyer, D.; Betschart, M. .; Keller, M. H.; Bates, M.; Zhuang, X.

Recently, Suchismita Roy et al. have explored how growth factors can modulate canonical G protein signaling cleft and P loop uncouple G proteins from GPCRs, leading to segregation of RTK-to-Gαi pathways from canonical For instance, the sequestration of G proteins from canonical GPCR-dependent pathways by growth factor J., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024). Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors

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).

Kathleen Caron. Check out the weekly Classified GPCR News from October 30 to November 4, 2023.

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.

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.

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

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

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

Faron-Gorecka, et al. 2019). 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.

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.

Biomed Pharmacother. 2018 Feb;98:222-232. doi: 10.1016/j.biopha.2017.12.056 Azam S, Haque ME, Jakaria M, ):11646-11664. doi: 10.3390/cimb46100691   Navarro G, Sotelo E, Raïch I, Loza MI, Brea J, Majellaro M.

GPCR contributor article Canonical chemokine receptors as scavenging “decoys” Shivani Sachdev, Brendan nanobody tethering Mechanistic insights into G-protein activation via phosphorylation mediated non-canonical Non-Peptide Small Molecule GLP-1 Receptor Agonist GSBR-1290 Crinetics Pharmaceuticals Appoints Robert 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