Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways
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.
Authors
- Marta Filizola (ORCID: https://orcid.org/0000-0002-4382-8276)
- Sławomir Filipek (ORCID: https://orcid.org/0000-0003-3147-3858)
- Ramón Guixà-González (ORCID: https://orcid.org/0000-0003-0397-9800)
- David Aranda-García (ORCID: https://orcid.org/0000-0002-5476-2903)
- Hugo Gutiérrez‐de‐Terán (ORCID: https://orcid.org/0000-0003-0459-3491)
- Esther Kellenberger (ORCID: https://orcid.org/0000-0002-9320-4840)
- Gáspár Pándy‐Szekeres (ORCID: https://orcid.org/0000-0002-7697-2696)
- David E. Gloriam (ORCID: https://orcid.org/0000-0002-4299-7561)
- Alessandro Nicoli (ORCID: https://orcid.org/0000-0001-6177-9749)
- Miguel Dieguez-Eceolaza (ORCID: https://orcid.org/0009-0008-9169-6416)
- Mariona Torrens‐Fontanals (ORCID: https://orcid.org/0000-0001-6233-8945)
- Johanna K. S. Tiemann (ORCID: https://orcid.org/0000-0001-7551-6245)
- Cathèrine Jacquemard (ORCID: https://orcid.org/0000-0002-9633-3429)
- David Sotillo-Núñez (ORCID: https://orcid.org/0009-0006-6414-8970)
- Jiafei Mao
- Maria Martí-Solano (ORCID: https://orcid.org/0000-0003-0373-8927)
- Mireia Jiménez‐Rosés (ORCID: https://orcid.org/0000-0002-4049-8670)
- Brian Medel-Lacruz (ORCID: https://orcid.org/0000-0003-2831-7731)
- Marta Lopez‐Balastegui (ORCID: https://orcid.org/0000-0002-6283-601X)
- Peter Kolb (ORCID: https://orcid.org/0000-0003-4089-614X)
- Toni Giorgino (ORCID: https://orcid.org/0000-0001-6449-0596)
- Irina G. Tikhonova (ORCID: https://orcid.org/0000-0002-6228-9431)
- Sergio Suarez Dou (ORCID: https://orcid.org/0000-0002-7929-9468)
- Alejandro Peralta-García
- Tianyi Ding (ORCID: https://orcid.org/0000-0002-1989-3705)
- Francho Nerín-Fonz (ORCID: https://orcid.org/0000-0002-5548-7608)
- Urszula Orzeł (ORCID: https://orcid.org/0000-0002-4002-7764)
- Tomasz Maciej Stępniewski (ORCID: https://orcid.org/0000-0002-6828-9192)
- Willem Jespers (ORCID: https://orcid.org/0000-0002-4951-9220)
- Jana Selent (ORCID: https://orcid.org/0000-0002-1844-4449)
- Peter W. Hildebrand (ORCID: https://orcid.org/0000-0003-0063-1104)
- Adrián García‐Recio (ORCID: https://orcid.org/0000-0002-7143-9075)
- Matthäus Drabek
- Dorota Latek (ORCID: https://orcid.org/0000-0002-0429-0637)
- Jakub Jakowiecki (ORCID: https://orcid.org/0000-0001-5882-1029)
- Antonella Di Pizio (ORCID: https://orcid.org/0000-0002-8520-5165)
- Aida Shahraki (ORCID: https://orcid.org/0000-0002-0507-8152)
- M. Madan Babu
- Adrián Morales-Pastor
- Víctor Jun-Yu-Lim
- Vicente Ledesma-Martin
- Oriol Canal (ORCID: https://orcid.org/0000-0001-6292-5947)
- Arnau Cordomi
Institutions
- Leiden University (NL)
- Universitat Autònoma de Barcelona (ES)
- Uppsala University (SE)
- University of Copenhagen (DK)
- Queen's University Belfast (GB)
- St. Jude Children's Research Hospital (US)
- University of Nottingham (GB)
- Philipps University of Marburg (DE)
- Universitat Pompeu Fabra (ES)
- University of Milan (IT)
- University of Cambridge (GB)
- Beijing National Laboratory for Molecular Sciences (CN)
- Laboratoire d'Innovation Thérapeutique (FR)
- Institute of Advanced Chemistry of Catalonia (ES)
- Hospital Del Mar (ES)
- Centre for Human Drug Research (NL)
- Municipal Institute for Medical Research (ES)
- Nanomaterials and Nanotechnology Research Center (ES)
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE)
- Acellera (Spain) (ES)
- National Research Council (IT)
- Hospital del Mar Research Institute (ES)
- University of Warsaw (PL)
- Technical University of Munich (DE)
- Université de Strasbourg (FR)
- University of Birmingham (GB)
- HUN-REN Research Centre for Natural Sciences (HU)
- Leipzig University (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-27
- DOI
- https://doi.org/10.1038/s41467-025-57034-y
- Citations
- 43
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 34.66
Funders
- American Lebanese Syrian Associated Charities
- European Commission
- Generalitat de Catalunya
- Lundbeckfonden
- Novo Nordisk
- Ministerio de Ciencia e Innovación
- Novo Nordisk Fonden
- H. Lundbeck A/S
- HORIZON EUROPE Framework Programme
- Leibniz-Gemeinschaft
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación