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)
Review
Immunology
Jianan Zhao, Kai Wei, Ping Jiang, Cen Chang, Lingxia Xu, Linshuai Xu, Yiming Shi, Shicheng Guo, Dongyi He
Summary: In this review, the role of G-protein-coupled receptors (GPCRs) in the mechanisms of rheumatoid arthritis (RA) is discussed, and the latest clinical trials on GPCR targeting are summarized, providing a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA.
FRONTIERS IN IMMUNOLOGY
(2022)
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
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)
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
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.
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
Biochemistry & Molecular Biology
Sandra Berndt, Ines Liebscher
Summary: SFKs are crucial regulators of cell proliferation, differentiation, and survival, with their expression strongly linked to cancer development and tumor progression. The regulation of SFKs through GPCR-mediated pathways is complex and may involve direct protein interactions or allosteric regulation by arrestins and G proteins. The potential direct interaction between GPCRs and SFKs could lead to a novel mechanism of SFK signaling and identification of new GPCR-SFK interactions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
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
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)
Review
Biochemistry & Molecular Biology
Jace Jones-Tabah
Summary: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the deterioration of dopaminergic neurons and motor impairment. Although there is no cure for PD, dopamine replacement therapies like L-DOPA can alleviate motor symptoms. However, non-motor symptoms and the progression of neurodegeneration still lack effective treatments. This review focuses on G protein-coupled receptors (GPCRs) as potential targets for treating PD and discusses various therapeutic strategies.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
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
Shanlin Rao, George T. Bates, Callum R. Matthews, Thomas D. Newport, Owen N. Vickery, Phillip J. Stansfeld
Article
Immunology
Maria Pia Alberione, Rebecca Moeller, Jared Kirui, Corinne Ginkel, Mandy Doepke, Luisa J. Stroeh, Jan-Philipp Machtens, Thomas Pietschmann, Gisa Gerold
MEDICAL MICROBIOLOGY AND IMMUNOLOGY
(2020)
Article
Pharmacology & Pharmacy
Annika H. Ruehlmann, Jannis Koerner, Ralf Hausmann, Nikolay Bebrivenski, Christian Neuhof, Silvia Detro-Dassen, Petra Hautvast, Carene A. Benasolo, Jannis Meents, Jan-Philipp Machtens, Guenther Schmalzing, Angelika Lampert
BRITISH JOURNAL OF PHARMACOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Annika Bartsch, Callum M. Ives, Christof Kattner, Florian Pein, Manuel Diehn, Mikio Tanabe, Axel Munk, Ulrich Zachariae, Claudia Steinem, Salome Llabres
Summary: This study highlights the importance of a single point mutation in the porin PorB from Neisseria meningitidis in affecting the binding and permeation of beta-lactam antibiotics, shedding light on the molecular basis of drug resistance in Gram-negative bacteria. Through various techniques including X-ray crystallography, electrophysiology, biomolecular simulation, and liposome swelling experiments, differences in drug interaction with PorB were identified, providing insights into potential broader applications in drug-porin interactions. This research improves the understanding of how mutations in porins contribute to drug resistance mechanisms.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Biochemistry & Molecular Biology
Claudia Alleva, Jan-Philipp Machtens, Daniel Kortzak, Ingo Weyand, Christoph Fahlke
Summary: Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and its transport is facilitated by the excitatory amino acid transporters (EAATs). These transporters utilize a complex stoichiometry to accumulate glutamate against concentration gradients and are also selective channels that open and close during the transport cycle. Recent research has uncovered the molecular mechanisms of coupled transport, substrate selectivity, and anion conduction in EAAT glutamate transporters, emphasizing the hairpin 2 gate as a key component in these functions.
NEUROCHEMICAL RESEARCH
(2022)
Article
Chemistry, Physical
Andrei Y. Kostritskii, Claudia Alleva, Saskia Coenen, Jan-Philipp Machtens
Summary: The tool g_elpot utilizes the smooth particle mesh Ewald method to quantify the electrostatics of biomolecules by calculating potential within water molecules that are explicitly present in biomolecular MD simulations. It can extract the global distribution of the electrostatic potential from MD trajectories and measure its time course in functionally important regions of a biomolecule, providing a deeper understanding of its role in biomolecular processes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Review
Biochemistry & Molecular Biology
Andrei Mironenko, Ulrich Zachariae, Bert L. de Groot, Wojciech Kopec
Summary: Potassium channels play critical roles in physiological processes by providing a selective permeation route for K+ ions. The structure of the selectivity filter has been determined at atomic resolution, but the molecular mechanism of K+ ions permeation remains unclear. Various proposed mechanisms of ion permeation are discussed, with critical evaluation against available data.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Andrei Y. Kostritskii, Jan-Philipp Machtens
Summary: The study identified that the main ion-conductive state of TMEM16 lipid scramblases is modulated by lipid headgroups, and different scramblase isoforms regulate ion selectivity through their amino-acid composition.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Physical
Owen N. Vickery, Phillip J. Stansfeld
Summary: Coarse-grained molecular dynamics offers a way to simulate macromolecular complexes at a reduced level of representation, allowing for longer timescales and larger simulations. This study presents an enhanced fragment-based protocol for converting such complexes to atomistic resolution, suitable for a variety of systems including integral membrane proteins. Evaluation of the approach on 11 system configurations shows promising results in accurately describing and balancing atomic-level descriptions of macromolecular complexes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Medicinal
Dominik Gurvic, Andrew G. Leach, Ulrich Zachariae
Summary: This study employs a data-driven approach to uncover the chemical features that influence the bioactivity of Gram-negative bacteria. The researchers discovered recurring chemical moieties that consistently improve activity, suggesting their potential use in optimizing compounds for increased Gram-negative uptake. These findings may expand the chemical space of broad-spectrum antibiotics and aid in the search for new antibiotic compound classes.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biophysics
Andrei Y. Kostritskii, Jan -Philipp Machtens
Summary: The ability to sense transmembrane voltage and understand the molecular basis of voltage coupling in voltage-gated sodium channels is crucial for understanding their physiological roles. This study provides new insights into the voltage-sensing mechanisms of Nav channels through high-resolution quantification of VSD electrostatics, revealing the importance of electric-field reshaping for voltage sensing.
BIOPHYSICAL JOURNAL
(2023)
Article
Biophysics
Abhishek Acharya, Kalyanashis Jana, Dominik Gurvic, Ulrich Zachariae, Ulrich Kleinekathofer
Summary: Predicting molecular permeability and evaluating the effect of molecular transformations on permeation rates are critical for the development of effective antibiotics. In this study, a computational approach using Brownian dynamics is proposed to obtain estimates of molecular permeability through a porin channel within hours. The method is significantly faster compared with previous approaches and shows good correlation with experimental results. The potential applications of this method in high-throughput screening for fast permeators are discussed.
BIOPHYSICAL JOURNAL
(2023)
Article
Physiology
Callum M. M. Ives, Neil J. J. Thomson, Ulrich Zachariae
Summary: Selective ion exchange across cellular membranes is important for cellular processes, especially Ca2+-mediated signaling. Maintaining strict Ca2+ concentration gradients across membranes is necessary due to the cytotoxic nature of elevated intracellular Ca2+ levels. The TRPV ion channels, particularly TRPV5 and TRPV6, play a crucial role in Ca2+ signaling by allowing selective permeation of Ca2+ ions. This study uses molecular dynamics simulations to investigate the mechanisms behind the high Ca2+ selectivity of some TRPV channels compared to others.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Article
Multidisciplinary Sciences
C. Alleva, K. Kovalev, R. Astashkin, M. Berndt, C. Baeken, T. Balandin, V Gordeliy, Ch Fahlke, J-P Machtens
Correction
Microbiology
Justin C. Deme, Steven Johnson, Owen Vickery, Amy Aron, Holly Monkhouse, Thomas Griffiths, Rory Hennell James, Ben C. Berks, James W. Coulton, Phillip J. Stansfeld, Susan M. Lea
NATURE MICROBIOLOGY
(2020)
