The path to the G protein-coupled receptor structural landscape: Major milestones and future directions.

Autor: Kogut-Günthel MM; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany., Zara Z; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.; Faculty of Science, University of South Bohemia in Ceske Budejovice, České Budějovice, Czech Republic., Nicoli A; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.; Professorship for Chemoinformatics and Protein Modelling, Department of Molecular Life Science, School of Life Science, Technical University of Munich, Freising, Germany., Steuer A; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.; Professorship for Chemoinformatics and Protein Modelling, Department of Molecular Life Science, School of Life Science, Technical University of Munich, Freising, Germany., Lopez-Balastegui M; Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute & Pompeu Fabra University, Barcelona, Spain., Selent J; Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute & Pompeu Fabra University, Barcelona, Spain., Karanth S; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany., Koehler M; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.; TUM Junior Fellow at the Chair of Nutritional Systems Biology, Technical University of Munich, Freising, Germany., Ciancetta A; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy., Abiko LA; Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, Basel, Switzerland., Hagn F; Structural Membrane Biochemistry, Bavarian NMR Center, Dept. Bioscience, School of Natural Sciences, Technical University of Munich, Munich, Germany.; Institute of Structural Biology (STB), Helmholtz Munich, Neuherberg, Germany., Di Pizio A; Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.; Professorship for Chemoinformatics and Protein Modelling, Department of Molecular Life Science, School of Life Science, Technical University of Munich, Freising, Germany.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Aug 29. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1111/bph.17314
Abstrakt: G protein-coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to the inside of the cell. They mediate the effects of various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, and are renowned drug targets. Advancements in structural biology techniques, including X-ray crystallography and cryo-electron microscopy (cryo-EM), have driven the elucidation of an increasing number of GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization and oligomerization, dichotomy between orthosteric and allosteric modulation, and the intricate interactions underlying signal transduction, providing insights into diverse ligand-binding modes and signalling pathways. However, a substantial portion of the GPCR repertoire and their activation states remain structurally unexplored. Future efforts should prioritize capturing the full structural diversity of GPCRs across multiple dimensions. To do so, the integration of structural biology with biophysical and computational techniques will be essential. We describe in this review the progress of nuclear magnetic resonance (NMR) to examine GPCR plasticity and conformational dynamics, of atomic force microscopy (AFM) to explore the spatial-temporal dynamics and kinetic aspects of GPCRs, and the recent breakthroughs in artificial intelligence for protein structure prediction to characterize the structures of the entire GPCRome. In summary, the journey through GPCR structural biology provided in this review illustrates how far we have come in decoding these essential proteins architecture and function. Looking ahead, integrating cutting-edge biophysics and computational tools offers a path to navigating the GPCR structural landscape, ultimately advancing GPCR-based applications.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: