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Deciphering conform...
Deciphering conformational selectivity in the A(2A) adenosine G protein-coupled receptor by free energy simulations
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- Jespers, Willem (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Leiden Acad Ctr Drug Res, Drug Discovery & Safety, Leiden, Netherlands.
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- Heitman, Laura H. (författare)
- Leiden Acad Ctr Drug Res, Drug Discovery & Safety, Leiden, Netherlands.;Oncode Inst, Leiden, Netherlands.
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- IJzerman, Adriaan P. (författare)
- Leiden Acad Ctr Drug Res, Drug Discovery & Safety, Leiden, Netherlands.
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- Sotelo, Eddy (författare)
- Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela, Spain.
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- Van Westen, Gerard J. P. (författare)
- Leiden Acad Ctr Drug Res, Drug Discovery & Safety, Leiden, Netherlands.
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- Åqvist, Johan (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik
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- Gutiérrez-de-Terán, Hugo (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2021-11-24
- 2021
- Engelska.
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 17:11
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Abstract
Ämnesord
Stäng
- Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A(2A) adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A(2A)AR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.
Ämnesord
- NATURVETENSKAP -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)
- NATURAL SCIENCES -- Computer and Information Sciences -- Bioinformatics (hsv//eng)
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