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Sci Rep. 2019 Oct 2;9(1):14199. doi: 10.1038/s41598-019-50752-6.

Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots.

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CADD, UCB BioPharma, 1420, Braine l'Alleud, Belgium.
Acellera, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003, Barcelona, Spain.
CADD, UCB Pharma, Slough, UK.
Computational Science Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003, Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010, Barcelona, Spain.
CADD, UCB BioPharma, 1420, Braine l'Alleud, Belgium.


G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state structures are scarce. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Efforts have been made to retrieve active state conformations starting from inactive structures, however to date this has not been possible without using an energy bias. Here, we reconstruct the activation pathways of the apo adenosine receptor (A2A), starting from an inactive conformation, by applying adaptive sampling MD combined with a goal-oriented scoring function. The reconstructed pathways reconcile well with experiments and help deepen our understanding of A2A regulatory mechanisms. Exploration of the apo conformational landscape of A2A reveals the existence of ligand-competent states, active intermediates and state-dependent cholesterol hotspots of relevance for drug discovery. To the best of our knowledge this is the first time an activation process has been elucidated for a GPCR starting from an inactive structure only, using a non-biased MD approach, opening avenues for the study of ligand binding to elusive yet pharmacologically relevant GPCR states.

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