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Kogut-Günthel, M.M.* ; Zara, Z.* ; Nicoli, A.* ; Steuer, A.* ; Lopez-Balastegui, M.* ; Selent, J.* ; Karanth, S.* ; Koehler, M.* ; Ciancetta, A.* ; Abiko, L.A.* ; Hagn, F. ; Di Pizio, A.*

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

Br. J. Pharmacol., DOI: 10.1111/bph.17314 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Review
Corresponding Author
Keywords Afm ; Gpcr ; Nmr ; Protein Structure Prediction ; Structural Biology; 2nd Extracellular Loop; High-resolution Structure; Allosteric Modulation; Crystal-structure; Beta-arrestin; Activation Mechanism; Dynamic Process; Drug Discovery; Binding-sites; Concise Guide
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Journal British Journal of Pharmacology
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants FAR