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
Biochemistry & Molecular Biology
Alfredo Ulloa-Aguirre, Teresa Zarinan, Eduardo Jardon-Valadez
Summary: This review discusses the mechanisms by which mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases. Special attention is given to misfolded GPCRs that regulate reproductive function, and promising therapeutic interventions targeting trafficking of these defective proteins to rescue their normal function are also described.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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)
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
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
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
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.
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
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
Wenjing Xu, Nathan P. Nelson-Maney, Laszlo Balint, Hyouk-Bum Kwon, Reema B. Davis, Danielle C. M. Dy, James M. Dunleavey, Brad St Croix, Kathleen M. Caron
Summary: This study identified four orphan GPCRs expressed at high levels in lymphatic endothelial cells. Using genetic engineering approaches in zebrafish and mice, the function of one of these receptors, GPRC5B, in lymphatic development was characterized. Expression of GPRC5B was found to be required for cell proliferation and viability in human primary LECs. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
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
Biochemical Research Methods
Chien Lee, Bo-Han Su, Yufeng Jane Tseng
Summary: Neural network-based protein modeling methods have made significant progress in recent years. This study compares the performance of these methods with the widely used template-based software Modeller in G-protein-coupled receptor (GPCR) protein modeling. The results show that, in cases where no good templates are available, the neural network-based methods outperformed the template-based method.
BRIEFINGS IN BIOINFORMATICS
(2022)
Review
Cardiac & Cardiovascular Systems
Alyssa Grogan, Emilio Y. Lucero, Haoran Jiang, Howard A. Rockman
Summary: G protein-coupled receptors (GPCRs) play key roles in cardiac health and disease, and are targeted for the treatment of cardiovascular diseases. Recent advancements in understanding GPCR signaling, regulation, and pharmacological properties have provided valuable insights.
CARDIOVASCULAR RESEARCH
(2023)
Review
Immunology
Nan Li, Shan Shan, Xiu-Qin Li, Ting-Ting Chen, Meng Qi, Sheng-Nan Zhang, Zi-Ying Wang, Ling-Ling Zhang, Wei Wei, Wu-Yi Sun
Summary: G protein-coupled receptor kinase 2 (GRK2) plays important roles in regulating signaling pathways associated with fibrotic diseases. Recent research suggests that GRK2 could be a potential therapeutic target for fibrotic diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Chemistry, Medicinal
Christofer S. Tautermann, Florian Binder, Frank H. Buettner, Christian Eickmeier, Dennis Fiegen, Ulrike Gross, Marc A. Grundl, Ralf Heilker, Scott Hobson, Stefan Hoerer, Andreas Luippold, Volker Mack, Florian Montel, Stefan Peters, Supriyo Bhattacharya, Nagarajan Vaidehi, Gisela Schnapp, Sven Thamm, Markus Zeeb
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Review
Chemistry, Multidisciplinary
Buddhinie S. Jayathilake, Supriyo Bhattacharya, Nagarajan Vaidehi, S. R. Narayanan
ACCOUNTS OF CHEMICAL RESEARCH
(2019)
Review
Cell Biology
Javier Garcia-Nafria, Christopher G. Tate
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2019)
Article
Multidisciplinary Sciences
Tony Warne, Patricia C. Edwards, Andrew S. Dore, Andrew G. W. Leslie, Christopher G. Tate
Review
Biochemistry & Molecular Biology
Supriyo Bhattacharya, Xingcheng Lin
Article
Oncology
Maciej Kujawski, Lin Li, Supriyo Bhattacharya, Patty Wong, Wen-Hui Lee, Lindsay Williams, Harry Li, Junie Chea, Kofi Poku, Nicole Bowles, Nagarajan Vaidehi, Paul Yazaki, John E. Shively
Article
Multidisciplinary Sciences
Vaithish Velazhahan, Ning Ma, Gaspar Pandy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, Nagarajan Vaidehi, Christopher G. Tate
Summary: GPCRs are divided into six classes, with structures of vertebrate GPCRs well understood but not of fungal class D GPCRs. This study reveals the structure of a class D GPCR in yeast and its coupling to G proteins, providing a template for the design of drugs to treat fungal diseases.
Article
Multidisciplinary Sciences
Na Wu, Agnieszka M. Olechwier, Cyrill Brunner, Patricia C. Edwards, Ching-Ju Tsai, Christopher G. Tate, Gebhard F. X. Schertler, Gisbert Schneider, Xavier Deupi, Renato Zenobi, Pikyee Ma
Summary: Developed high-sensitivity, high-throughput MALDI-MS method to study the interaction between GPCRs and signaling partners, focusing on GPCR-G protein complex formation. Studied over 70 ligand-GPCR-partner protein combinations to determine selectivity and binding affinities, demonstrating the potential for broad use in screening GPCR-targeting drugs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Javier Garcia-Nafria, Christopher G. Tate
Summary: GPCRs are the largest single family of cell surface receptors encoded by the human genome, playing pivotal roles in coordinating cellular systems throughout the human body and serving as ideal drug targets. Structural biology has been crucial in defining receptor activation mechanisms and signaling pathways, with recent advances in cryo-EM opening up new possibilities for GPCR structural biology research. While cryo-EM has advantages in determining GPCR structures, X-ray crystallography remains valuable for speedily determining multiple structures of the same receptor bound to different ligands, an essential step in structure-based drug design.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Article
Biochemistry & Molecular Biology
Arin Nam, Atish Mohanty, Supriyo Bhattacharya, Sourabh Kotnala, Srisairam Achuthan, Kishore Hari, Saumya Srivastava, Linlin Guo, Anusha Nathan, Rishov Chatterjee, Maneesh Jain, Mohd W. Nasser, Surinder Kumar Batra, Govindan Rangarajan, Erminia Massarelli, Herbert Levine, Mohit Kumar Jolly, Prakash Kulkarni, Ravi Salgia
Summary: This study developed a mathematical approach based on game theory to model the response of non-small cell lung cancer cells to cisplatin treatment. The findings suggest that dynamic interactions and group behavior play a role in drug resistance, with tolerant cells displaying a 'persister-like' behavior and educating sensitive cells to evade chemotherapy. Furthermore, intermittent chemotherapy may be a better treatment strategy to reduce the emergence of tolerant cells in lung cancer.
Article
Multidisciplinary Sciences
Vaithish Velazhahan, Ning Ma, Nagarajan Vaidehi, Christopher G. Tate
Summary: The fungal class D1 G-protein-coupled receptor Ste2 differs from mammalian GPCRs in the arrangement of its transmembrane helices and its coupling mechanism to the heterotrimeric G protein Gpa1-Ste2-Ste18. This receptor lacks conserved sequence motifs associated with the activation of class A GPCRs, suggesting a different activation mechanism. The determined structures of Ste2 in different conformations bound to agonist and antagonist revealed that Ste2 is indeed activated differently from other GPCRs. The movement of transmembrane helices H6 and H7 upon agonist binding facilitates G protein coupling.
Article
Medicine, General & Internal
Prakash Kulkarni, Atish Mohanty, Supriyo Bhattacharya, Sharad Singhal, Linlin Guo, Sravani Ramisetty, Tamara Mirzapoiazova, Bolot Mambetsariev, Sandeep Mittan, Jyoti Malhotra, Naveen Gupta, Pauline Kim, Razmig Babikian, Swapnil Rajurkar, Shanmuga Subbiah, Tingting Tan, Danny Nguyen, Amartej Merla, Sudarsan Kollimuttathuillam, Tanyanika Phillips, Peter Baik, Bradford Tan, Pankaj Vashi, Sagun Shrestha, Benjamin Leach, Ruchi Garg, Patricia L. Rich, F. Marc Stewart, Evan Pisick, Ravi Salgia
Summary: Drug resistance is a major obstacle in cancer treatment. However, the use of a 'Team Medicine' approach and the development of new therapeutic strategies, such as intermittent therapy, based on eco-evolutionary principles, have shown promising results. Incorporating these strategies into clinical protocols can enhance the precision of personalized medicine.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Medicine, General & Internal
Sravani Ramisetty, Prakash Kulkarni, Supriyo Bhattacharya, Arin Nam, Sharad S. Singhal, Linlin Guo, Tamara Mirzapoiazova, Bolot Mambetsariev, Sandeep Mittan, Jyoti Malhotra, Evan Pisick, Shanmuga Subbiah, Swapnil Rajurkar, Erminia Massarelli, Ravi Salgia, Atish Mohanty
Summary: Translational research in medicine involves collaboration between scientists from different disciplines to apply knowledge from basic sciences to clinical practice. This approach, known as 'Team Medicine', focuses on addressing specific medical goals through partnership between basic science researchers and clinicians. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as an example, this study demonstrates how a 'Team Science' approach was used to identify a previously approved compound that can alleviate cisplatin resistance in NSCLC. It also highlights the potential of a 'Team Medicine' approach in understanding resistance mechanisms and developing strategies to overcome drug resistance in NSCLC.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Anastasiia Gusach, Javier Garcia-Nafria, Christopher G. Tate
Summary: In the past three years (2020-2022), more GPCR structures have been determined than in the previous twenty years (2000-2019), primarily utilizing single-particle cryo-EM to determine large enough GPCR complexes. This review highlights the structural advancements in understanding promiscuous G protein coupling, the coupling of G protein receptor kinase and L-arrestins to GPCRs, and GPCR dimerization. The use of gene fusions, nanobodies, and Fab fragments to facilitate the structure determination of small GPCRs in the inactive state by single-particle cryo-EM is also discussed.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Meeting Abstract
Biotechnology & Applied Microbiology
Shirley Li, Maciej Kujawski, Lin Li, Harry Li, Supriyo Bhattacharya, Vaidehi Nagarajan, Paul Yazaki, Pamela J. Bjorkman, John Zaia, John E. Shively