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)
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Endocrinology & Metabolism
Fanhua Wang, Mingyao Liu, Ning Wang, Jian Luo
Summary: This review discusses the role of G-protein coupled receptors (GPCRs) in osteoarthritis (OA), including the pathophysiological processes involved, preclinical and clinical trial data, and the challenges in developing therapies targeting GPCRs for OA.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Pharmacology & Pharmacy
Kate F. Byrne, Ajay Pal, James F. Curtin, John C. Stephens, Gemma K. Kinsella
Summary: The focus of the review is on G-protein-coupled receptor (GPCR) targets, with chemokine, cannabinoid, and dopamine receptors showing promise. Further research is needed on potential targets such as MC4R, adhesion receptors, LPA, and Smo receptors to develop new drug-screening strategies for safe and effective GBM therapies.
DRUG DISCOVERY TODAY
(2021)
Review
Biochemistry & Molecular Biology
Dekel David, Ziv Bentulila, Merav Tauber, Yair Ben-Chaim
Summary: GPCRs are involved in signal transduction processes, and although they span the cell membrane, they have not been considered to be regulated by membrane potential. Recent studies, however, have shown that several GPCRs are voltage regulated. This review discusses the advances in understanding the voltage dependence of GPCRs, the suggested molecular mechanisms, and the possible physiological roles.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Ramon Cierco Jimenez, Nil Casajuana-Martin, Adrian Garcia-Recio, Lidia Alcantara, Leonardo Pardo, Mercedes Campillo, Angel Gonzalez
Summary: The study analyzed 119,069 natural variants in human olfactory receptors, revealing a significant diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a considerable number of changes occurring at the structurally conserved regions. Mutations in positions linked to the conserved GPCR activation mechanism were highlighted, which could imply phenotypic variation in olfactory perception.
Review
Pharmacology & Pharmacy
Sergi Ferre, Francisco Ciruela, Carmen W. Dessauer, Javier Gonzalez-Maeso, Terence E. Hebert, Ralf Jockers, Diomedes E. Logothetis, Leonardo Pardo
Summary: The study proposes the concept of GPCR-effect assemblies (GEMMAs), which are pre-assembled before receptor activation and allow more efficient interactions between specific signaling components. This offers an alternative model to the conventional collision coupling model and explains the differential properties of GPCRs in different cellular environments.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Chemistry, Multidisciplinary
Xin-heng He, Chong-zhao You, Hua-liang Jiang, Yi Jiang, H. Eric Xu, Xi Cheng
Summary: G protein-coupled receptors (GPCRs) are important drug targets that play crucial roles in various physiological processes. Although extensive efforts have been made in the field of structural biology, a significant number of GPCR structures remain unsolved due to their structural instability. Recently, AlphaFold2 has been developed as a tool to predict the structure models of GPCRs and other functionally important proteins. However, our evaluation reveals several differences between the predicted models and experimental structures, such as the assembly of domains, shape of ligand-binding pockets, and conformation of binding interfaces. These differences hinder the use of predicted structure models in functional studies and structure-based drug design, where reliable high-resolution structural information is required.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Pharmacology & Pharmacy
Jaana van Gastel, Hanne Leysen, Jan Boddaert, Laura Vangenechten, Louis M. Luttrell, Bronwen Martin, Stuart Maudsley
Summary: Aging is a complex molecular process that affects almost all tissue systems in humans and is the primary risk factor for neurodegenerative disorders, cardiovascular disease, and Type 2 diabetes. With the current focus on GPCR-targeted therapeutics dominating the pharmacopeia, searching for effective anti-aging treatments in this area may be beneficial. A nuanced understanding of GPCR signaling diversity could lead to the development of therapeutics with selective signaling activities to impact the complex aberrations of the aging process.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Wojciech Pietrus, Rafal Kurczab, Dagmar Stumpfe, Andrzej J. Bojarski, Juergen Bajorath
Summary: The study showed that introducing fluorine can significantly increase ligand potency, but the effect of fluorination on affinity varies depending on the fluorination position. Fluorination of the aromatic ring at the ortho position is favorable for potency enhancement, while fluorination of aliphatic fragments more often leads to a decrease in biological activity.
Article
Chemistry, Multidisciplinary
Yunfang Xiong, Ran Ke, Qingyu Zhang, Wenjun Lan, Wanjun Yuan, Karol Nga Ieng Chan, Tom Roussel, Yifan Jiang, Jing Wu, Shuai Liu, Alice Sze Tsai Wong, Joong Sup Shim, Xuanjun Zhang, Ruiyu Xie, Nelson Dusetti, Juan Iovanna, Nagy Habib, Ling Peng, Leo Tsz On Lee
Summary: This study reports the effective modulation of a GPCR for cancer treatment using small activating RNAs (saRNAs) for the first time. The saRNAs promote the expression of MAS1, a GPCR that counteracts cancer cell proliferation and migration. By enhancing MAS1 expression, these saRNAs suppress tumorigenesis and inhibit tumor progression in multiple cancer models. This research not only provides a new strategy for cancer therapy by targeting the renin-angiotensin system, but also offers a new avenue to modulate GPCR signaling through RNA activation.
Review
Engineering, Biomedical
Yuhong Jiang, Yuke Li, Xiujuan Fu, Yue Wu, Rujing Wang, Mengnan Zhao, Canquan Mao, Sanjun Shi
Summary: The translation article introduces the interaction between G protein-coupled receptors (GPCRs) and nanotechnology, as well as how nanotechnology can improve the efficacy and safety of GPCR-related drugs. Nanotechnology can encapsulate GPCR ligands to construct synthetic nano-GPCRs and precisely initiate sustained endosomal signal transduction through nanoparticles. Moreover, nanoparticles can enhance the potency of delivery systems by actively targeting specific cells through ligand-receptor binding and receptor-dependent endocytosis.
ACTA BIOMATERIALIA
(2023)
Article
Biochemistry & Molecular Biology
Laura Lemel, Katarzyna Niescierowicz, M. Dolores Garcia-Fernandez, Leonardo Darre, Thierry Durroux, Marta Busnelli, Mylene Pezet, Fabrice Rebeille, Juliette Jouhet, Bernard Mouillac, Carmen Domene, Bice Chini, Vadim Cherezov, Christophe J. Moreau
Summary: The study revealed a stable binding of cholesterol molecules to OXTR in the presence of orthosteric ligands, leading to a positive cross-regulation between cholesterol and orthosteric ligands, which preserves the activity of the receptor in cholesterol-depleted membranes.
JOURNAL OF LIPID RESEARCH
(2021)
Review
Cell Biology
Tomasz Boczek, Joanna Mackiewicz, Marta Sobolczyk, Julia Wawrzyniak, Malwina Lisek, Bozena Ferenc, Feng Guo, Ludmila Zylinska
Summary: Schizophrenia is a common psychiatric illness characterized by psychosis episodes, with G protein-coupled receptors (GPCRs) playing a critical role in its development and treatment. Dysfunctions in neurotransmitter-GPCRs signaling likely underly the complex symptoms of schizophrenia, offering potential for new avenues in drug development.
Article
Biochemistry & Molecular Biology
Felix Hohendanner, Ashok Prabhu, Nicola Wilck, Verena Stangl, Burkert Pieske, Karl Stangl, Till F. Althoff
Summary: G(q)-signaling promotes arrhythmogenic atrial Ca2+-release and atrial fibrillation (AF). Targeting this pathway, preferably using G(q)-selective receptor ligands, may be a promising approach for the treatment and prevention of AF, while avoiding adverse effects on the ventricles.
Review
Biophysics
Karim Fahmy, Thomas P. Sakmar
Summary: The centenary of H. Gobind Khorana's birth provides an opportunity to review the origins and evolution of biophysical methodology and molecular genetics technology used to study membrane proteins. Interdisciplinary collaboration in the Khorana laboratory led to significant advances in the biophysical study of membrane proteins, particularly in understanding the molecular mechanisms of energy transduction by bacteriorhodopsin and signal transduction by rhodopsin. This review focuses on the application of molecular genetics approaches to engineer alterations in membrane protein structures, enabling detailed studies of membrane proteins.
BIOPHYSICAL REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Leonie Hartl, Joris J. T. H. Roelofs, Frederike Dijk, Maarten F. Bijlsma, JanWillem Duitman, C. Arnold Spek
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a serious disease with limited treatment options. The low expression of CCAAT/Enhancer-Binding Protein Delta (C/EBP delta) in PDAC is associated with poor patient survival and lymph node involvement. However, C/EBP beta and C/EBP gamma can partly compensate for the loss of C/EBP delta and improve patient outcomes. C/EBP beta also serves as a new predictor for reduced lymph node involvement.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Nele Klatte, Denis C. C. Shields, Clement Agoni
Summary: During coronavirus infection, the non-structural proteins nsp3, nsp4, and nsp6 are crucial for the formation of double-membrane vesicles and membrane pairing. The interaction between nsp3 and nsp4 is stable, with the linker region of nsp4 playing a key role. Understanding the functional importance of the nsp4 linker region may have implications for controlling coronavirus infection.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Mireille Elodie Tsitokana, Pierre-Andre Lafon, Laurent Prezeau, Jean-Philippe Pin, Philippe Rondard
Summary: Therapeutic antibodies for the treatment of central nervous system diseases have been extensively studied, resulting in approved monoclonal antibodies for brain disease therapies. Additionally, non-invasive antibody-based imaging approaches have been explored for biomarker detection in brain cancers. However, the low ability of antibodies to cross the blood-brain barrier has led to the investigation of single-domain antibodies (sdAbs) as an alternative. While the brain uptake of these small antibodies is initially low, there is a growing number of studies reporting brain-penetrating sdAbs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Ilana B. Kotliar, Emily Lorenzen, Jochen M. Schwenk, Debbie L. Hay, Thomas P. Sakmar
Summary: G protein-coupled receptors (GPCRs) interact with a variety of membrane proteins, but the extent and mechanisms of these interactions are not well understood. RAMPs, a class of GPCR-interacting proteins, have been extensively studied. Recent research suggests that GPCR-RAMP interactions may be more widespread than previously thought. This review summarizes the latest techniques for discovering GPCR-RAMP interactions and their functional consequences, and discusses future research prospects.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Jordan M. Mattheisen, Jaina S. Wollowitz, Thomas Huber, Thomas P. Sakmar
Summary: We developed a luciferase-based reporter assay for site-specific bioorthogonal labeling of expressed G protein-coupled receptors (GPCRs) in live cells. The assay compared amber codon suppression efficiency, receptor functionality, and efficiency of different bioorthogonal labeling chemistries. We used three different noncanonical amino acids to incorporate into a GPCR, resulting in successful labeling and functional assessment of the engineered mutants in live cells.
Letter
Critical Care Medicine
C. Arnold Spek, Jan Willem Duitman
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Review
Oncology
Leonie Hartl, JanWillem Duitman, Maarten F. Bijlsma, C. Arnold Spek
Summary: CCAAT/Enhancer-Binding Protein delta (C/EBP8) is a transcription factor involved in differentiation and inflammation. Its aberrant expression has been associated with different cancers. While initially thought to act as a tumor suppressor, it is now widely accepted that C/EBP8 contributes to tumor-promoting effects, such as inflammation, hypoxia adaptation, and blood vessel recruitment. This review summarizes the research on C/EBP8 in cancer and seeks to explain conflicting results.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ilana B. Kotliar, Emilie Ceraudo, Kevin Kemelmakher-Liben, Deena A. Oren, Emily Lorenzen, Tea Dodig-Crnkovic, Mizuho Horioka-Duplix, Thomas Huber, Jochen M. Schwenk, Thomas P. Sakmar
Summary: The interaction between MRGPRX4 and RAMP2 can regulate the signaling pathway and cell surface expression of cholestatic itch, suggesting potential therapeutic implications for future drug development in treating cholestatic itch.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Jordan M. Mattheisen, Chris Limberakis, Roger B. Ruggeri, Matthew S. Dowling, Christopher W. am Ende, Emilie Ceraudo, Thomas Huber, Christopher L. McClendon, Thomas P. Sakmar
Summary: We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance their potency and enable fragment-based drug screening in cell-based systems.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Biochemistry & Molecular Biology
Indrani Bera, Michael O'Sullivan, Darragh Flynn, Denis C. Shields
Summary: Legume seed protein is less digestible than animal protein, possibly due to defenses against herbivores. Germination increases proteolysis and digestibility by reducing anti-nutrient protease inhibitors, activating proteases, and breaking down storage proteins. Further research is needed to understand the mechanisms behind improved digestibility and guide the development of more digestible food preparations.
Article
Multidisciplinary Sciences
Leo Dahl, Ilana B. Kotliar, Annika Bendes, Tea Dodig-Crnkovic, Samuel Fromm, Arne Elofsson, Mathias Uhlen, Thomas P. Sakmar, Jochen M. Schwenk
Summary: A multiplexed immunoassay was developed to test the selectivity of over 400 anti-GPCR antibodies. The results showed that about 61% of the antibodies were selective, 11% bound off-target, and 28% did not bind to any GPCR. It was also found that on-target antibodies had longer, more disordered antigens and were less buried in the interior of GPCR proteins compared to other antibodies.
Article
Biochemistry & Molecular Biology
Clement Agoni, Ilias Stavropoulos, Anna Kirwan, Margharitha M. Mysior, Therese Holton, Tilen Kranjc, Jeremy C. Simpson, Helen M. Roche, Denis C. Shields
Summary: This study identified and synthesized peptides from milk protein Alpha-S1-casein that were predicted to be cell-penetrating. The peptides showed cell penetrating behavior without affecting cell homeostatic mechanisms. Further investigation is warranted to explore their potential bioactivities.
Article
Biochemistry & Molecular Biology
A. Zheng, N. Huang, D. Bean, S. Rayapaneni, Jude Deeney, M. Sagar, James A. Hamilton
Summary: The purpose of this study is to investigate heart-fatty acid binding protein (H-FABP) leakage from cardiomyocytes as a quantitative measure of cell membrane damage and to test healing by Resolvin E1 (RVE1) as a potential therapeutic for patients with inflammatory diseases. The study demonstrates that H-FABP is a sensitive and reliable biomarker for measuring cardiomyocyte damage induced by lipopolysaccharide (LPS) and healing by RvE1. HFABP is also a valuable measure for patients with increased inflammation disease comorbidities.
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS
(2023)
Article
Biochemistry & Molecular Biology
Etienne J. Slapak, Mouad el Mandili, Marieke S. Ten Brink, Alexander Kros, Maarten F. Bijlsma, C. Arnold Spek
Summary: Pancreatic adenocarcinoma (PDAC) is difficult to treat with chemotherapy and has a poor survival rate. Targeted drug delivery approaches using mesoporous silica nanoparticles (MSNs) have shown promise in killing PDAC cells in vitro. However, when tested in clinically relevant models, off-target toxicity was observed. Optimized ADAM9-responsive MSNs (OPT-MSNs) were developed to minimize off-target cytotoxicity while still efficiently killing PDAC cells. In a preclinical PDAC xenograft model, paclitaxel-loaded OPT-MSNs reduced organ damage and leukopenia but did not exhibit antitumor activity. This study highlights the challenges in translating MSN-based tumor-targeting strategies into effective clinical treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
