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Article

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2-4, 14195 Berlin, Germany
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9728; https://doi.org/10.3390/ijms21249728
Received: 22 November 2020 / Revised: 16 December 2020 / Accepted: 18 December 2020 / Published: 20 December 2020
G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors. View Full-Text
Keywords: GPCR; biased signaling; molecular dynamics; serotonin receptors; virtual screening; conformational descriptor; pharmacophore; drug design GPCR; biased signaling; molecular dynamics; serotonin receptors; virtual screening; conformational descriptor; pharmacophore; drug design
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MDPI and ACS Style

Denzinger, K.; Nguyen, T.N.; Noonan, T.; Wolber, G.; Bermudez, M. Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors. Int. J. Mol. Sci. 2020, 21, 9728. https://doi.org/10.3390/ijms21249728

AMA Style

Denzinger K, Nguyen TN, Noonan T, Wolber G, Bermudez M. Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors. International Journal of Molecular Sciences. 2020; 21(24):9728. https://doi.org/10.3390/ijms21249728

Chicago/Turabian Style

Denzinger, Katrin, Trung Ngoc Nguyen, Theresa Noonan, Gerhard Wolber, and Marcel Bermudez. 2020. "Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors" International Journal of Molecular Sciences 21, no. 24: 9728. https://doi.org/10.3390/ijms21249728

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