Review
Biochemistry & Molecular Biology
Haoyi Ge, Huixia Wang, Benxun Pan, Dandan Feng, Canyong Guo, Lingyun Yang, Dongsheng Liu, Kurt Wuethrich
Summary: GPCRs are a membrane protein family present in higher organisms, including humans, and play a key role in cellular responses and physiological functions. Understanding the structure and dynamics of GPCRs is crucial for drug design and involves the modulation of extrinsic ligands and intracellular binding partners.
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
Chemistry, Multidisciplinary
Longmei Li, Jin Zhang, Wenjing Sun, Weimin Gong, Changlin Tian, Pan Shi, Chaowei Shi
Summary: This study used F-19 solution NMR spectroscopy to investigate the conformational changes of G proteins upon interaction with detergent mimicking membrane and receptor. The results showed that there are two equilibrium states in the Gain apo states, and the interaction with detergents accelerates the conformational transformation.
CHINESE CHEMICAL LETTERS
(2022)
Review
Chemistry, Organic
Diana Gimenez, Aoife Phelan, Cormac D. Murphy, Steven L. Cobb
Summary: F-19 NMR is widely used in the field of chemical biology for synthesizing new fluorinated probes, monitoring protein interactions, structural analysis, etc. It remains relevant for investigating the biosynthesis and biodegradation of fluorinated organic compounds.
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2021)
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
Chemistry, Multidisciplinary
Bingjie Zhang, Shanshan Li, Wenqing Shui
Summary: G protein-coupled receptors (GPCRs) are a large family of proteins that play significant roles in cellular and physiological responses. Post-translational modifications (PTMs) of GPCRs, such as glycosylation, phosphorylation, ubiquitination and palmitoylation, have important regulatory functions in receptor folding, biosynthesis, trafficking, dimerization and signaling. This review provides an overview of PTMs in GPCRs, focusing on their types, locations, cross talk and dynamic regulation, which can shed light on the molecular basis of GPCRs and contribute to structure-based drug discovery.
FRONTIERS IN CHEMISTRY
(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)
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)
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
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
Biochemistry & Molecular Biology
Bryan T. Martin, Robert D. Malmstrom, Rommie E. Amaro, Kurt Wuthrich
Summary: The study found that the OCRE domains of the splicing factors RBM5 and RBM10 exhibit symmetric H-1 NMR spectra for tyrosines at 25 degrees C, but some tyrosines show decreased flipping frequency at 4 degrees C. By combining H-1 NMR spectroscopy and molecular dynamics simulations, the researchers determined the range of tyrosine ring-flip frequencies in these domains.
Article
Biochemistry & Molecular Biology
Bram Mylemans, Hiroki Noguchi, Els Deridder, Eveline Lescrinier, Jeremy R. H. Tame, Arnout R. D. Voet
Article
Biochemistry & Molecular Biology
Huixia Wang, Wanhui Hu, Dongsheng Liu, Kurt Wuthrich
Summary: GLP-1R and GCGR are human receptors activated by GLP-1 and GCG, involved in metabolism regulation. NMR studies provide insights into their molecular structures and interactions with ligands.
Review
Biochemical Research Methods
Gilbert S. Omenn
Summary: The HUPO Human Proteome Project celebrates its 10th anniversary by achieving the milestone of confident detection of proteins from 90% of predicted protein-coding genes. This global project has influenced data-sharing, quality assurance, and issued stringent guidelines for detecting missing proteins. The project's impact is highlighted in special issues of Nature Communications and Journal of Proteome Research.
MOLECULAR & CELLULAR PROTEOMICS
(2021)
Article
Biochemistry & Molecular Biology
Matthew T. Eddy, Bryan T. Martin, Kurt Wuthrich
Summary: In drug design, GPCR partial agonists can fine-tune receptor output levels, and NMR studies have revealed distinct structural differences between partial and full agonist complexes, indicating different structural rearrangements for different signaling pathways.
Biographical-Item
Biochemical Research Methods
Kurt Wuthrich
JOURNAL OF MAGNETIC RESONANCE
(2021)
Article
Biochemical Research Methods
Kurt Wuthrich
Summary: The development of protein structure determination by NMR in solution from 1968 to 1992 was driven by identifying NMR-accessible parameters and developing new experimental methods. Breakthroughs during the years 1976-1984 include the development of NOE experiments, solving the phase problem, generating distance geometry algorithms, and introducing two-dimensional NMR for improved spectral resolution.
JOURNAL OF MAGNETIC RESONANCE
(2021)
Article
Chemistry, Multidisciplinary
Xiaoyan Wang, Dongsheng Liu, Ling Shen, Fahui Li, Yongze Li, Lingyun Yang, Tiandan Xu, Houchao Tao, Deqiang Yao, Lijie Wu, Kunio Hirata, Laura M. Bohn, Alexandros Makriyannis, Xiaohong Liu, Tian Hua, Zhi-Jie Liu, Jiangyun Wang
Summary: A method for genetic incorporation of an unnatural amino acid into a cannabinoid receptor has been developed, revealing a previously unrecognized pre-active state through F-19 NMR and X-ray crystallography methods. An allosteric modulation model is proposed to explain the distinct behavior of the allosteric modulator Org27569. This site-specific F-19 NMR labeling method is a powerful tool for decoding the mechanism of GPCR allosteric modulation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Marina D. Larionova, Lijie Wu, Elena Eremeeva, Pavel Natashin, Dmitry Gulnov, Elena Nemtseva, Dongsheng Liu, Zhi-Jie Liu, Eugene S. Vysotski
Summary: Coelenterazine-v (CTZ-v) is a suitable substrate for deep tissue imaging with Renilla luciferase, but Ca2+-regulated photoproteins activated by CTZ-v have low bioluminescence activity and are unsuitable for calcium imaging. The low bioluminescence activity of obelin-v is attributed to the low efficiency of generating an electronic excited state, possibly due to small changes in the substrate microenvironment at the active site.
Review
Biochemistry & Molecular Biology
Haoyi Ge, Huixia Wang, Benxun Pan, Dandan Feng, Canyong Guo, Lingyun Yang, Dongsheng Liu, Kurt Wuethrich
Summary: GPCRs are a membrane protein family present in higher organisms, including humans, and play a key role in cellular responses and physiological functions. Understanding the structure and dynamics of GPCRs is crucial for drug design and involves the modulation of extrinsic ligands and intracellular binding partners.
Article
Multidisciplinary Sciences
Benxun Pan, Dongsheng Liu, Lingyun Yang, Kurt Wuthrich
Summary: Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists reveal differences in the width of the orthosteric ligand binding groove. F-19-NMR experiments with the neurokinin 1 receptor (NK1R) show transient structure fluctuations with amplitudes up to at least 6 angstrom. The data suggest extensive promiscuity of initial ligand binding and large-scale floating motions of GPCR transmembrane helices in the lipid bilayer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Lingyun Yang, Dongsheng Liu, Kurt Wuethrich
Summary: This review discusses several NMR approaches used to probe the dynamics and intermolecular interactions of GPCRs. NMR spectroscopy provides unique information on the dynamics of GPCR structures at physiological temperature, contributing to our understanding of GPCR biology and providing foundations for rational drug design.
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
(2022)
Article
Multidisciplinary Sciences
Huixia Wang, Wanhui Hu, Tiandan Xu, Ya Yuan, Dongsheng Liu, Kurt Wuthrich
Summary: Crystal and cryo-EM structures of GLP-1R and GCGR bound with their peptide ligands were obtained, confirming the importance of the ECD in ligand binding. Paramagnetic NMR relaxation enhancement measurements revealed GLP-1 selectively interacts with the extracellular surface of GLP-1R. The study also showed cross-reactivity between GLP-1R and GCGR with glucagon and GLP-1, respectively, which has implications for medical treatments.
Letter
Medicine, Research & Experimental
Yanliu Fan, Xi Lin, Benxun Pan, Bo Chen, Dongsheng Liu, Kurt Wuethrich, Fei Xu