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| Página principal > Artículos > Artículos publicados > Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways |
(Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Hospital del Mar d'Investigacions Mèdiques) (Acellera Labs) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Hospital del Mar d'Investigacions Mèdiques) (Queen's University Belfast) (University of Strasbourg) (Leiden University) (University of Birmingham) (University of Munich) (Universität Leipzig) (Universitat Pompeu Fabra) (Universitat Pompeu Fabra) (Universitat Pompeu Fabra) (HUN-REN Research Center for Natural Sciences) (University of Copenhagen) (University of Strasbourg) (University of Warsaw) (Institut de Química Avançada de Catalunya) (Research Center in Nanomaterials and Nanotechnology) (Queen's University Belfast) (Medical University Leipzig) (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica)) (St. Jude Children's Research Hospital (Memphis, Estats Units d'Amèrica)) (Technical University of Munich) (University of Warsaw) (University of Marburg) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (University of Milan) (University of Cambridge) (Institut Hospital del Mar d'Investigacions Mèdiques)
| Fecha: | 2025 |
| Resumen: | 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. |
| Ayudas: | Generalitat de Catalunya 2020FI_SDU/487 Instituto de Salud Carlos III CD22/00007 Generalitat de Catalunya 2021/SGR-00046 Generalitat de Catalunya 2022/DI-00112 Ministerio de Ciencia, Innovación y Universidades FPU20/03069 European Commission 101080465 Agencia Estatal de Investigación PID2022-137161OB-I00 Agencia Estatal de Investigación PID2023-150793OB-I00 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Publicado en: | Nature communications, Vol. 16 (February 2025) , art. 2020, ISSN 2041-1723 |
