Dataset Information

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT_2B Receptors.

ABSTRACT: 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 ?-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT_2B 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.

SUBMITTER: Denzinger K

PROVIDER: S-EPMC7767279 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT<sub>2B</sub> Receptors.

Denzinger Katrin K Nguyen Trung Ngoc TN Noonan Theresa T Wolber Gerhard G Bermudez Marcel M

International journal of molecular sciences 20201220 24

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 c ...[more]

PMID: 33419260

Similar Datasets

Project description:Whether synaptic transmission is excitatory or inhibitory depends, to a large extent, on whether the ion channels that open upon binding the released neurotransmitter conduct cations or anions. The mechanistic basis of the opposite charge selectivities of Cys-loop receptors has only recently begun to emerge. It is now clear that ionized side chains-whether pore-facing or buried-in the first ?-helical turn of the second transmembrane segments underlie this phenomenon and that the electrostatics of backbone atoms are not critically involved. Moreover, on the basis of electrophysiological observations, it has recently been suggested that not only the sign of charged side chains but also their conformation are crucial determinants of cation-anion selectivity. To challenge these ideas with the chemical and structural rigor that electrophysiological observations naturally lack, we performed molecular dynamics, Brownian dynamics, and electrostatics calculations of ion permeation. To this end, we used structural models of the open-channel conformation of the ?1 glutamate-gated Cl- channel and the ?1 glycine receptor. Our results provided full support to the notion that the conformation of charged sides chains matters for charge selectivity. Indeed, whereas some rotamers of the buried arginines at position 0' conferred high selectivity for anions, others supported the permeation of cations and anions at similar rates or even allowed the faster permeation of cations. Furthermore, we found that modeling glutamates at position -1' of the anion-selective ?1 glycine receptor open-state structure-instead of the five native alanines-switches charge selectivity also in a conformation-dependent manner, with some glutamate rotamers being much more effective at conferring selectivity for cations than others. Regarding pore size, we found that the mere expansion of the pore has only a minimal impact on cation-anion selectivity. Overall, these results bring to light the previously unappreciated impact of side-chain conformation on charge selectivity in Cys-loop receptors.

Dataset Information

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT_2B Receptors.

Publications

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT<sub>2B</sub> Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Publications

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT<sub>2B</sub> Receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT_2B Receptors.