Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways

David Aranda-García, Tomasz Maciej Stepniewski, Mariona Torrens-Fontanals, Adrian García-Recio, Marta Lopez-Balastegui, Brian Medel-Lacruz, Adrián Morales-Pastor, Alejandro Peralta-García, Miguel Dieguez-Eceolaza, David Sotillo-Nuñez, Tianyi Ding, Matthäus Drabek, Célien Jacquemard, Jakub Jakowiecki, Willem Jespers, Mireia Jiménez-Rosés, Víctor Jun-Yu-Lim, Alessandro Nicoli, Urszula Orzel, Aida Shahraki, Johanna K. S. Tiemann, Vicente Ledesma-Martin, Francho Nerín-Fonz, Sergio Suárez-Dou, Oriol Canal, Gáspár Pándy-Szekeres, Jiafei Mao, David E. Gloriam, Esther Kellenberger, Dorota Latek, Ramon Guixà-González, Hugo Gutiérrez- de-Terán, Irina G. Tikhonova, Peter W. Hildebrand, Marta Filizola, M. Madan Babu, Antonella Di Pizio, Slawomir Filipek, Peter Kolb, Arnau Cordomi, Toni Giorgino, Maria Marti-Solano and Jana Selent ()
Additional contact information
David Aranda-García: Pompeu Fabra University (UPF)
Tomasz Maciej Stepniewski: Hospital del Mar Medical Research Institute (IMIM)
Mariona Torrens-Fontanals: Pompeu Fabra University (UPF)
Adrian García-Recio: Hospital del Mar Medical Research Institute (IMIM)
Marta Lopez-Balastegui: Pompeu Fabra University (UPF)
Brian Medel-Lacruz: Pompeu Fabra University (UPF)
Adrián Morales-Pastor: Pompeu Fabra University (UPF)
Alejandro Peralta-García: Pompeu Fabra University (UPF)
Miguel Dieguez-Eceolaza: Pompeu Fabra University (UPF)
David Sotillo-Nuñez: Pompeu Fabra University (UPF)
Tianyi Ding: Queen’s University Belfast
Matthäus Drabek: University of Marburg
Célien Jacquemard: University of Strasbourg
Jakub Jakowiecki: University of Warsaw
Willem Jespers: Leiden University
Mireia Jiménez-Rosés: University of Birmingham and University of Nottingham
Víctor Jun-Yu-Lim: University of Marburg
Alessandro Nicoli: Leibniz Institute for Food Systems Biology at the Technical University of Munich
Urszula Orzel: University of Warsaw
Aida Shahraki: University of Marburg
Johanna K. S. Tiemann: Universität Leipzig
Vicente Ledesma-Martin: Pompeu Fabra University (UPF)
Francho Nerín-Fonz: Pompeu Fabra University (UPF)
Sergio Suárez-Dou: Pompeu Fabra University (UPF)
Oriol Canal: Pompeu Fabra University (UPF)
Gáspár Pándy-Szekeres: University of Copenhagen
Jiafei Mao: Institute of Chemistry Chinese Academy of Science (ICCAS)
David E. Gloriam: University of Copenhagen
Esther Kellenberger: University of Strasbourg
Dorota Latek: University of Warsaw
Ramon Guixà-González: Institute for Advanced Chemistry of Catalonia (IQAC-CSIC)
Hugo Gutiérrez- de-Terán: Uppsala University, Biomedical Center
Irina G. Tikhonova: Queen’s University Belfast
Peter W. Hildebrand: Medical University Leipzig
Marta Filizola: Icahn School of Medicine at Mount Sinai
M. Madan Babu: St. Jude Children’s Research Hospital
Antonella Di Pizio: Leibniz Institute for Food Systems Biology at the Technical University of Munich
Slawomir Filipek: University of Warsaw
Peter Kolb: University of Marburg
Arnau Cordomi: Universitat Autònoma de Barcelona (UAB)
Toni Giorgino: National Research Council of Italy
Maria Marti-Solano: University of Cambridge
Jana Selent: Pompeu Fabra University (UPF)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract G protein-coupled receptors (GPCRs) constitute a functionally diverse protein family and are targets for a broad spectrum of pharmaceuticals. Technological progress in X-ray crystallography and cryogenic electron microscopy has enabled extensive, high-resolution structural characterisation of GPCRs in different conformational states. However, as highly dynamic events underlie GPCR signalling, a complete understanding of GPCR functionality requires insights into their conformational dynamics. Here, we present a large dataset of molecular dynamics simulations covering 60% of currently available GPCR structures. Our analysis reveals extensive local “breathing” motions of the receptor on a nano- to microsecond timescale and provides access to numerous previously unexplored receptor conformational states. Furthermore, we reveal that receptor flexibility impacts the shape of allosteric drug binding sites, which frequently adopt partially or completely closed states in the absence of a molecular modulator. We demonstrate that exploring membrane lipid dynamics and their interaction with GPCRs is an efficient approach to expose such hidden allosteric sites and even lateral ligand entrance gateways. The obtained insights and generated dataset on conformations, allosteric sites and lateral entrance gates in GPCRs allows us to better understand the functionality of these receptors and opens new therapeutic avenues for drug-targeting strategies.

Date: 2025
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DOI: 10.1038/s41467-025-57034-y

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