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. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

Department of Chemical Pharmaceutical and Agricultural Sciences University of Ferrara Ferrara Italy

Faculty of Science University of South Bohemia in Ceske Budejovice České Budějovice Czech Republic

Focal Area Structural Biology and Biophysics Biozentrum University of Basel Basel Switzerland

Institute of Structural Biology Helmholtz Munich Neuherberg Germany

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

Research Programme on Biomedical Informatics Hospital del Mar Medical Research Institute and Pompeu Fabra University Barcelona Spain

Structural Membrane Biochemistry Bavarian NMR Center Dept Bioscience School of Natural Sciences Technical University of Munich Munich Germany

TUM Junior Fellow at the Chair of Nutritional Systems Biology Technical University of Munich Freising Germany

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