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)
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
Krzysztof Jozwiak, Anita Plazinska
Summary: Studies on different receptors belonging to class A of GPCRs reveal specific molecular mechanisms behind ligand directed signaling, including the role of important residues, the impact of ligand structural features on signaling, and the key interactions between ligands and receptors.
Review
Pharmacology & Pharmacy
Hsin-Yung Yen, Ali Jazayeri, Carol Robinson
Summary: GPCRs are important drug targets due to their involvement in physiological processes. Mass spectrometry techniques, such as HDX-MS and native-MS, provide opportunities to investigate GPCR pharmacology and discover new drugs. This review highlights the potential of MS techniques for in-depth investigations of GPCR biology.
PHARMACOLOGICAL REVIEWS
(2023)
Review
Pharmacology & Pharmacy
Stephen J. Hill, Laura E. Kilpatrick
Summary: Equilibrium binding assays are commonly used in drug discovery to evaluate drug-receptor interactions, but there is increasing interest in studying the kinetics of these interactions. Drugs can induce conformational changes in the orthosteric binding site, leading to alterations in the association and dissociation rates of orthosteric ligands. This review provides an overview of how fluorescent ligand technologies are used to study ligand-receptor kinetics in living cells and the insights they offer into conformational changes induced by drugs targeting cell surface receptors.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mingcheng Qian, Zhengyang Sun, Xin Chen, Serge Van Calenbergh
Summary: This review provides an overview of the design strategy of bivalent ligands for G protein-coupled receptors (GPCRs) and mainly focuses on their application in studying and detecting GPCR dimerization in vitro and in vivo. Bivalent ligands have specific properties and are capable of binding to GPCR homodimers or heterodimers simultaneously, showing specific signal transduction compared to monovalent ligands.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Mark T. Agasid, Lars Sorensen, Leonhard H. Urner, Jun Yan, Carol Robinson
Summary: The use of mass spectrometry to study G protein-coupled receptors has revealed insights into sodium binding and ligand-induced changes, providing valuable information for understanding GPCR function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Review
Pharmacology & Pharmacy
Reid H. J. Olsen, Justin G. English
Summary: Enzymatic and cellular signaling biosensors are powerful tools for understanding complex biological systems. G protein-coupled receptors (GPCRs) are extensively studied using biosensors, which have expanded our knowledge of this important class of proteins. Transducer biosensors that measure receptor coupling and selectivity, with a focus on receptor association and activation of heterotrimeric signaling complexes, are of particular importance.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Saravanan Konda Mani, Ramesh Thiyagarajan, Olli Yli-Harja, Meenakshisundaram Kandhavelu, Akshaya Murugesan
Summary: The human GPR17 receptor acts as a biomarker for neurological diseases. Two isoforms, long and short, of GPR17 are found in human brain tissue. The structure of the long isoform has been studied, but the structure and activation mechanism of the short isoform remain unclear. In this study, the researchers modeled the structure of the short isoform and identified two distinct ligand binding sites. The binding of the endogenous ligand UDP was found to be stronger in both binding sites, suggesting its importance in the signaling and communication properties of GPR17. These findings may contribute to the development of targeted therapies for neurological diseases.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Laura E. Kilpatrick, Stephen J. Hill
Summary: Some G protein-coupled receptors (GPCRs) are not evenly expressed within the plasma membrane but may form distinct signaling microdomains, localizing GPCRs in close proximity with other membrane proteins and intracellular signaling partners. Techniques like fluorescence correlation spectroscopy (FCS) are needed for probing the molecular mechanisms governing GPCR pharmacology within these domains.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Review
Pharmacology & Pharmacy
Rafael Franco, Paula Morales, Gemma Navarro, Nadine Jagerovic, Irene Reyes-Resina
Summary: The complexity of cannabinoid CB2 receptor pharmacology is highlighted by the fact that drugs can lead to different signaling outputs based on the receptor conformation and interactions with other proteins or membrane lipids. Understanding the binding mode of CB2R ligands is crucial for optimizing signaling effects and therapeutic potential.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Hee-Kyung Park, Lan Phuong Nguyen, Thai Uy Nguyen, Minyeong Cho, Huong Thi Nguyen, Sunghoon Hurh, Hong-Rae Kim, Jae Young Seong, Cheol Soon Lee, Byung-Joo Ham, Jong-Ik Hwang
Summary: CXCL12 is an essential chemokine for organ development and homeostasis, and its receptor CXCR4 is widely expressed on target cells. Multiple splice variants of CXCR4 have been identified, and these variants have different expression patterns and cellular functions. The variants may also interact with each other during cellular responses to CXCL12. Therefore, further investigation of the functional roles of CXCR4 variants could contribute to the development of novel drug interventions.
Article
Immunology
Naotaka Tsutsumi, Qianhui Qu, Masa Mavri, Maibritt S. Baggesen, Shoji Maeda, Deepa Waghray, Christian Berg, Brian K. Kobilka, Mette M. Rosenkilde, Georgios Skiniotis, K. Christopher Garcia
Summary: The study reveals that the EBV receptor BILF1 has constitutive signaling activity promoting immunosuppression and virulence independent of ligand availability. This has implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
Article
Biology
Michael A. Skuhersky, Fei Tao, Rui Qing, Eva Smorodina, David Jin, Shuguang Zhang
Summary: The accurate predictions of protein structures by AlphaFold2 have revolutionized biology, particularly structural biology. This study compared native chemokine receptor structures with their water-soluble QTY variants, showing high structural similarity despite significant sequence differences. Insights gained from this study may facilitate the design of water-soluble membrane proteins and other aggregated proteins.
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
Rob Hill, Meritxell Canals
Summary: Morphine and other opioids are widely used for pain treatment, but their side effects limit their use. Developing opioids with fewer side effects is a major research focus, but translating promising candidates from the lab to the clinic remains challenging.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Gastroenterology & Hepatology
Jesse J. DiCello, Simona E. Carbone, Ayame Saito, Vi Pham, Agata Szymaszkiewicz, Arisbel B. Gondin, Sadia Alvi, Kiliana Marique, Priyank Shenoy, Nicholas A. Veldhuis, Jakub Fichna, Meritxell Canals, Arthur Christopoulos, Celine Valant, Daniel P. Poole
Summary: This study investigates the modulation of delta opioid receptor in the enteric nervous system using allosteric modulators, demonstrating the potential of positive allosteric modulation as a pharmacological approach to enhance opioid receptor signaling and suppress colonic motility. The findings suggest that allosteric modulation of opioid receptor signaling could be a therapeutic strategy for conditions such as irritable bowel syndrome.
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Rob Hill, Andrew C. Kruegel, Jonathan A. Javitch, J. Robert Lane, Meritxell Canals
Summary: The study found differential effects of Mitragynine and its metabolite, 7-OH Mitragynine, on mouse respiration and anti-nociception. Mitragynine showed a ceiling effect on respiratory depression, while 7-OH Mitragynine had dose-dependent effects. Inhibition of CYP3A reduced the respiratory depressant effects and anti-nociception induced by Mitragynine, but had no effect on the effects of 7-OH Mitragynine. These findings suggest that metabolic saturation may contribute to the improved safety profile of Mitragynine.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hendrik J. Brink, Rick Riemens, Stephanie Thee, Berend Beishuizen, Daniel da Costa Pereira, Maikel Wijtmans, Iwan de Esch, Martine J. Smit, Albertus H. de Boer
Summary: In this study, a fragment-based drug screening approach was used to identify a PPI stabilizer targeting 14-3-3. The stabilizer was found to cooperatively stabilize 14-3-3 and enhance its binding to client proteins. This finding provides a tool compound for investigating the interactions between 14-3-3 and client proteins.
Article
Multidisciplinary Sciences
Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie Anderson, Lisa M. McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigne, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman
Summary: NMR experiments on ACKR3 revealed that the recruitment of beta-arrestins is associated with conformational exchange at key regions of the receptor, and identified an allosteric hub in the core receptor that coordinates transitions among different conformational states, guiding beta-arrestin recruitment.
Article
Education & Educational Research
Mirella Jongsma, Danny J. Scholten, Jacqueline E. van Muijlwijk-Koezen, Martijn Meeter
Summary: This paper conducts a meta-analysis comparing the effectiveness of online and offline peer feedback in higher education, finding that online peer feedback is more effective. Moreover, online peer feedback is more effective in assessing competence and students generally have a positive attitude towards it, although there are also some downsides.
JOURNAL OF EDUCATIONAL COMPUTING RESEARCH
(2023)
Letter
Biochemistry & Molecular Biology
Hendrik J. Brink, Jeffrey R. van Senten, Ingrid J. De Vries-van Leeuwen, Daniel da Costa Pereira, Sander R. Piersma, Connie R. Jimenez, Federica Centorrino, Christian Ottmann, Marco Siderius, Martine J. Smit, Albertus H. de Boer
Summary: CIP2A is an oncoprotein that is overexpressed in many types of cancer, and it stabilizes other oncoproteins to promote tumor development. This study discovered that the penultimate residue Ser904 in the C-terminus of CIP2A can be phosphorylated, allowing it to bind with the regulatory protein 14-3-3. Additionally, a protein-protein interaction stabilizer called FC-A can enhance the phosphorylation of Ser904 and increase the association between CIP2A and 14-3-3. This provides a new potential method to modulate the activity of CIP2A.
ACS CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Justine S. Paradis, Xiang Feng, Brigitte Murat, Robert E. Jefferson, Badr Sokrat, Martyna Szpakowska, Mireille Hogue, Nick D. Bergkamp, Franziska M. Heydenreich, Martine J. Smit, Andy Chevigne, Michel Bouvier, Patrick Barth
Summary: This article presents a computational approach for predicting receptor self-associations and designing receptor oligomers with various quaternary structures and signaling properties. Using this approach, the chemokine receptor CXCR4 dimers were successfully designed to have different conformations and abilities to activate distinct intracellular signaling proteins. The study also revealed the existence of a bias switch at the dimer interface of several G protein-coupled receptors, including CXCR4, mu-Opioid, and type-2 Vasopressin receptors, that selectively control the activation of G proteins vs beta-arrestin-mediated pathways.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Matyas A. Bittenbinder, Nick D. Bergkamp, Julien Slagboom, Jan Paul M. Bebelman, Nicholas R. Casewell, Marco H. Siderius, Martine J. Smit, Jeroen Kool, Freek J. Vonk
Summary: Snakebite envenoming is a significant public health concern with high mortality rates. Snake venoms can have various harmful effects on the body, including tissue damage. This study presents a workflow using fluorescently labeled ECM components to investigate the degradation of ECM caused by snake venom. This approach provides valuable insights into the mechanisms of proteolytic venom components and could aid in the development of effective snakebite treatments.
Article
Pharmacology & Pharmacy
Rob Hill, Julie Sanchez, Laura Lemel, Mirjana Antonijevic, Yselkla Hosking, Shailesh N. Mistry, Andrew C. Kruegel, Jonathan A. Javitch, J. Robert Lane, Meritxell Canals
Summary: This study evaluated the effects of three novel opioids on respiratory depression and analgesia, and compared these measurements with their in vitro efficacy. The results showed that these opioids can induce respiratory depression and analgesia at certain doses, but there are differences in potency and duration of effect among the novel opioids.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Chemistry, Physical
Michail Papadourakis, Hryhory Sinenka, Pierre Matricon, Jerome Henin, Grace Brannigan, Laura Perez-Benito, Vineet Pande, Herman van Vlijmen, Chris de Graaf, Francesca Deflorian, Gary Tresadern, Marco Cecchini, Zoe Cournia
Summary: This article reviews the progress in alchemical free energy calculations of membrane proteins, focusing on best practices and critical aspects of simulations on G-protein-coupled receptors, ion channels, transporters, and protein-lipid interactions. The study reveals the valuable application of alchemical free energy calculations in drug discovery for membrane-associated proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Nick D. Bergkamp, Jeffrey R. van Senten, Hendrik J. Brink, Maarten P. Bebelman, Jelle van den Bor, Tugce S. Cobanoglu, Kasper Dinkla, Johannes Koester, Gunnar Klau, Marco Siderius, Martine J. Smit
Summary: The G-protein coupled receptor US28 encoded by human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas. In this study, it was found that US28 enhances signaling mediated by sphingosine-1-phosphate (S1P), promoting glioblastoma cell proliferation and survival. The study also uncovers the roles of S1P and CIP2A in US28-mediated exacerbation of glioblastoma.
Article
Multidisciplinary Sciences
Maarten P. Bebelman, Irfan M. Setiawan, Nick D. Bergkamp, Jeffrey R. van Senten, Caitrin Crudden, Jan Paul M. Bebelman, Frederik J. Verweij, Guillaume van Niel, Marco Siderius, D. Michiel Pegtel, Martine J. Smit
Summary: The HCMV-encoded chemokine receptor US28 plays a role in various aspects of the viral life cycle and immune evasion by scavenging chemokines from HCMV-infected cells. It localizes to late endosomal compartments called multivesicular bodies (MVBs) and can be secreted on exosomes through fusion with the plasma membrane. The exosomal release of US28 contributes to chemokine scavenging and immune evasion by HCMV.
Article
Biochemical Research Methods
Jelle van den Bor, Nick D. Bergkamp, Stephanie M. Anbuhl, Francoise Dekker, Dehan Comez, Claudia V. Perez Almeria, Reggie Bosma, Carl W. White, Laura E. Kilpatrick, Stephen J. Hill, Marco Siderius, Martine J. Smit, Raimond Heukers
Summary: The use of nanobodies and NanoBRET methods allows for real-time monitoring of nanobody-receptor binding, predicting the therapeutic potential of ligands targeting disease-associated membrane proteins, which is significant for drug research.
CELL REPORTS METHODS
(2023)
Letter
Oncology
Gamal A. Wakileh, Philipp Bierholz, Mara Kotthoff, Margaretha A. Skowron, Felix Bremmer, Alexa Stephan, Stephanie M. Anbuhl, Raimond Heukers, Martine J. Smit, Philipp Stroebel, Daniel Nettersheim
Summary: This study identified a nanobody-drug-conjugate targeting CXCR4 as a potential therapeutic option for GCT. Furthermore, this study shed light on the functional role of the CXCR4 / CXCR7 / CXCL12-signaling cascade in GCT, demonstrating an important influence on proliferation and migration.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2023)
