Review
Biochemistry & Molecular Biology
Alexander O. Shpakov
Summary: Allosteric regulation plays a critical role in the functioning of GPCRs and their signaling pathways. The complexity of allosteric effects caused by various regulators determines the multiplicity and topology of allosteric sites in GPCRs. These sites are involved in the regulation of receptor activity, GPCR-complex formation, and endocytosis. They are also targets for synthetic allosteric regulators and modulators. The review provides an overview of the principles and mechanisms of GPCRs allosteric regulation, the diversity of allosteric sites, and the endogenous and synthetic allosteric regulators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Jyrki P. Kukkonen
Summary: Recent data indicates cooperative effects between identical orthosteric binding sites in a G-protein-coupled receptor dimer. A mathematical model was created to test this concept, showing that even a neutral receptor ligand can allosterically affect agonist binding through the orthosteric binding site.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Cell Biology
Joshua D. Frenster, Hediye Erdjument-Bromage, Gabriele Stephan, Niklas Ravn-Boess, Shuai Wang, Wenke Liu, Devin Bready, Jordan Wilcox, Bjorn Kieslich, Manuel Jankovic, Caroline Wilde, Susanne Horn, Norbert Strater, Ines Liebscher, Torsten Schoneberg, David Fenyo, Thomas A. Neubert, Dimitris G. Placantonakis
Summary: This study identifies PTK7 as an extracellular binding partner of GPR133 in glioblastoma, and shows that PTK7 enhances GPR133 signaling by binding to the N-terminal fragment of GPR133. This interaction is potentially relevant to the pathogenesis of glioblastoma.
Article
Biochemistry & Molecular Biology
Liudi Zhang, Jesse I. Mobbs, Lauren T. May, Alisa Glukhova, David M. Thal
Summary: G-protein coupled receptors (GPCRs) are important therapeutic targets for human disease. Allosteric modulators, which target alternative binding sites, offer opportunities for new therapeutics.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Evan van Aalst, Benjamin J. Wylie
Summary: Cholesterol serves as an allosteric modulator of G protein-coupled receptor function, influencing receptor-ligand interactions and signal transduction. CCR3, a chemokine receptor, plays a vital role in cell trafficking and is implicated in cancer metastasis and inflammatory conditions. However, there is a lack of experimental evidence linking the functional states of CCR3 to the molecular mechanisms of cholesterol-receptor cooperativity.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Cell Biology
Kanako Miyano, Yuki Yoshida, Shigeto Hirayama, Hideki Takahashi, Haruka Ono, Yoshiyuki Meguro, Sei Manabe, Akane Komatsu, Miki Nonaka, Takaaki Mizuguchi, Hideaki Fujii, Yoshikazu Higami, Minoru Narita, Yasuhito Uezono
Summary: The study found that OT acts as a positive allosteric modulator of KOR and MOR, enhancing G protein signaling without affecting beta-arrestin signaling.
Article
Chemistry, Multidisciplinary
Hsin-Yung Yen, Idlir Liko, Wanling Song, Parth Kapoor, Fernando Almeida, Joanna Toporowska, Karolina Gherbi, Jonathan T. S. Hopper, Steven J. Charlton, Argyris Politis, Mark S. P. Sansom, Ali Jazayeri, Carol Robinson
Summary: This study presents a mass spectrometry-based approach to investigate the biased signaling and allosteric modulation of the beta(1)-adrenergic receptor in response to different ligands. The researchers discovered that isoprenaline can act as a biased agonist and that endogenous zinc ions enhance the binding between the receptor and G(s) proteins.
Review
Biochemistry & Molecular Biology
Andreas Bock, Marcel Bermudez
Summary: Bias agonism in GPCRs is likely a result of preferential allosteric coupling from the ligand binding pocket to a specific transducer, leading to selective activation of desired signaling pathways and potentially reducing side effects.
Review
Chemistry, Multidisciplinary
Keith M. Olson, John R. Traynor, Andrew Alt
Summary: Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) present desirable drug targets due to their potential to produce fewer on-target side effects and improved selectivity compared to orthosteric drugs. Peptides and proteins, deriving from endogenous protein-protein interactions, intramolecular receptor contacts, endogenous peptides, and exogenous libraries, serve as underappreciated sources for identifying AM leads, offering advantages such as high affinity and bioactivity along with disadvantages like poor metabolic stability. Peptidomimetics combine the advantages of both peptides and small molecules, mimicking peptide chemical features responsible for bioactivity while enhancing druggability.
FRONTIERS IN CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Steven S. An, Joseph M. Salvino, Raymond B. Penn, Roger S. Armen, Charles P. Scott, Jeffrey L. Benovic
Summary: A negative allosteric modulator, DFPQ, was found to selectively inhibit beta-arrestin recruitment to beta(2)AR without affecting its coupling to Gs. This may provide a strategy to improve the functional consequences of beta(2)AR activation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Prashant Donthamsetti, David B. Konrad, Belinda Hetzler, Zhu Fu, Dirk Trauner, Ehud Y. Isacoff
Summary: G protein-coupled receptors (GPCRs) are common drug discovery targets, but the complexity of in vivo receptor activation has hindered drug development. Photopharmacology offers the potential to control drug action using light. Recent advances include a photoswitchable allosteric agonist that selectively activates receptors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Dongchen An, Steve Peigneur, Jan Tytgat
Summary: The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. WIN55,212-2, a non-selective agonist of CB1 and CB2, activates CB1 and CB2 at low concentrations and blocks GIRK1/2 at high concentrations.
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Chemistry, Medicinal
Kien Tran, Robin Van den Hauwe, Xavier Sainsily, Pierre Couvineau, Jerome Cote, Louise Simard, Marco Echevarria, Alexandre Murza, Alexandra Serre, Lea Theroux, Sabrina Saibi, Lounes Haroune, Jean-Michel Longpre, Olivier Lesur, Mannix Auger-Messier, Claude Spino, Michel Bouvier, Philippe Sarret, Steven Ballet, Eric Marsault
Summary: Side-chain-constrained amino acids were used to modify apelin-13 (Ape13), resulting in analogues with higher affinity for the apelin receptor (APJ). Substitutions at the Pro12 and Phe13 positions, particularly using 1Nal, Trp, Aia, D-Tic, Db(z)g, and D-alpha-Me-Tyr(OBn) residues, proved to be beneficial in enhancing binding affinity and signaling profile. Compounds 47 and 53 emerged as the most potent Ape13 analogues, with improved pharmacokinetic properties and activation of the G alpha(12) pathway.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Elodie Blondel-Tepaz, Marie Leverve, Badr Sokrat, Justine S. Paradis, Milena Kosic, Kusumika Saha, Cedric Auffray, Evelyne Lima-Fernandes, Alessia Zamborlini, Anne Poupon, Louis Gaboury, Jane Findlay, George S. Baillie, Herve Enslen, Michel Bouvier, Stephane Angers, Stefano Marullo, Mark G. H. Scott
Summary: The protein beta-arrestin2 plays a critical role in regulating the Mdm2-p53 signaling axis by promoting the nuclear-cytoplasmic shuttling of Mdm2 and enhancing p53 signaling. While beta-arrestin2 can be SUMOylated, it is the non-covalent interaction between SUMO and beta-arrestin2, mediated by a SUMO interaction motif (SIM), that is essential for its cytonuclear trafficking function. Depletion of the RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub leads to defective beta-arrestin2 nuclear entry, inhibiting its ability to displace Mdm2 from the nucleus and enhancing p53 signaling in cancer cells.
Article
Multidisciplinary Sciences
Shane C. Wright, Viktoriya Lukasheva, Christian Le Gouill, Hiroyuki Kobayashi, Billy Breton, Samuel Mailhot-Larouche, Elodie Blondel-Tepaz, Nichelle Antunes Vieira, Claudio Costa-Neto, Madeleine Heroux, Nevin A. Lambert, Lucas Tabajara Parreiras-e-Silva, Michel Bouvier
Summary: This study uses bioluminescence resonance energy transfer (BRET) to investigate the translocation and activity of Gq in endosomes, revealing different mechanisms underlying Gq activity at the plasma membrane and endosomes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Pharmacology & Pharmacy
Peter Kolb, Terry Kenakin, Stephen P. H. Alexander, Marcel Bermudez, Laura M. Bohn, Christian S. Breinholt, Michel Bouvier, Stephen J. Hill, Evi Kostenis, Kirill A. Martemyanov, Rick R. Neubig, H. Ongun Onaran, Sudarshan Rajagopal, Bryan L. Roth, Jana Selent, Arun K. Shukla, Martha E. Sommer, David E. Gloriam
Summary: GPCRs regulate various physiological processes and their effects depend on the pairing of a receptor and a ligand. Ligands that induce biased signalling can lead to better drug effects and fewer side effects. However, ligand bias is complex, making it necessary to develop guidelines for designing and reporting biased signalling experiments.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ramakotaiah Mulamreddy, William D. Lubell
Summary: This paper reports the synthesis of 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids from L-serine, and discusses their potential in peptide mimicry.
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Alexander S. Hauser, Charlotte Avet, Claire Normand, Arturo Mancini, Asuka Inoue, Michel Bouvier, David E. Gloriam
Summary: Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors coupled to G proteins, but there are differences in the reported G protein couplings among recent large-scale datasets. This study presents a common coupling map that uncovers novel couplings, GPCR-G protein selectivity, and the comparison of co-coupling and co-expression of G proteins with phylogenetic relationships. These findings will advance receptor research and cellular signaling, and contribute to the development of safer drugs.
Article
Biology
Charlotte Avet, Arturo Mancini, Billy Breton, Christian Le Gouill, Alexander S. Hauser, Claire Normand, Hiroyuki Kobayashi, Florence Gross, Mireille Hogue, Viktoriya Lukasheva, Stephane St-Onge, Marilyn Carrier, Madeleine Heroux, Sandra Morissette, Eric B. Fauman, Jean-Philippe Fortin, Stephan Schann, Xavier Leroy, David E. Gloriam, Michel Bouvier
Summary: This study presents a set of BRET sensors to monitor the activation of G protein subtypes without modifying the receptors or G proteins. Profiling 100 therapeutically relevant human GPCRs resulted in pathway-specific concentration-response curves, revealing a diversity of coupling profiles.
Article
Pharmacology & Pharmacy
Franziska Marie Heydenreich, Bianca Plouffe, Aurelien Rizk, Dalibor Milic, Joris Zhou, Billy Breton, Christian Le Gouill, Asuka Inoue, Michel Bouvier, Dmitry B. Veprintsev
Summary: By modeling G protein activation as a Michaelis-Menten reaction, we have developed a novel method for quantifying signaling bias. V2R activates, or at least engages, G proteins from all G protein subfamilies, including Gi2, Gz, Gq, G12, and G13. Their relative activation may explain its Gs-independent signaling.
MOLECULAR PHARMACOLOGY
(2022)
Editorial Material
Biochemistry & Molecular Biology
William D. Lubell
Article
Biochemistry & Molecular Biology
Valeria Burghi, Justine S. Paradis, Adam Officer, Sendi Rafael Adame-Garcia, Xingyu Wu, Edda S. F. Matthees, Benjamin Barsi-Rhyne, Dana J. Ramms, Lauren Clubb, Monica Acosta, Pablo Tamayo, Michel Bouvier, Asuka Inoue, Mark von Zastrow, Carsten Hoffmann, J. Silvio Gutkind
Summary: This study focuses on the role of beta-arrestins in G protein-coupled receptor (GPCR) signaling. It is found that while G proteins are essential for GPCR signaling, beta-arrestins play a more prominent role in signal compartmentalization and modulation of gene expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xiaozheng Wei, Sitan Diarra, Antoine Douchez, Juliana C. Cunico Dallagnol, Terence E. Hebert, David Chatenet, William D. Lubell
Summary: The study of Urotensin II receptor (UT) modulators can help us understand the roles of the endogenous cyclic peptide ligands urotensin II (UII) and urotensin II-related peptide (URP) in disease etiology. By designing and synthesizing a series of compounds, selective modulators of hUII and URP activities were discovered, which can affect biological processes such as vasoconstriction.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Shane C. Wright, Aikaterini Motso, Stefania Koutsilieri, Christian M. Beusch, Pierre Sabatier, Alessandro Berghella, Elodie Blondel-Tepaz, Kimberley Mangenot, Ioannis Pittarokoilis, Despoina-Christina Sismanoglou, Christian Le Gouill, Jesper V. Olsen, Roman A. Zubarev, Nevin A. Lambert, Alexander S. Hauser, Michel Bouvier, Volker M. Lauschke
Summary: This study investigates the subcellular location of GLP-1R signaling events and reveals associations between signaling profiles and adverse drug reactions, providing important insights for rational drug design and improving the therapeutic potential of GLP-1R agonists.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Anh Minh Thao Nguyen, Moran Shalev-Benami, Chloe Rosa-Teijeiro, Ana Victoria Ibarra-Meneses, Ada Yonath, Anat Bashan, Charles L. Jaffe, Martin Olivier, Christopher Fernandez-Prada, William D. Lubell
Summary: A strategy for preparing potent anisomycin derivatives with reduced host toxicity has been revealed by assessing structure-activity relationships for anti-protozoan activity. Different modifications of the alcohol, amine, and aromatic functional groups have been studied, and it was found that introducing substituents at the para-phenol moiety of anisomycin can maintain the anti-protozoan potency without significant loss of activity against the host.
Article
Chemistry, Organic
Zhihong Luo, Lei Xu, Xiaomin Tang, Xuejun Zhao, Tong He, William D. Lubell, Jinqiang Zhang
Summary: In this study, novel all-hydrocarbon cross-linked aza-stapled peptides were designed and synthesized for the first time. These peptides exhibited increased anti-tumor activity, binding affinities, and cell membrane permeability compared to their linear counterparts.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)