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WIREs Comput Mol Sci
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The role of metal ions in G protein‐coupled receptor signalling and drug discovery

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Abstract Metal ions, such as Na+, Mg2+, Ca2+, and Zn2+, are highly abundant in biological systems. For many G protein‐coupled receptors (GPCRs), metal ions, especially Na+, have been found to stabilize the receptors' inactivate state preventing receptor activation. Besides this role, recent studies indicated that metal ions can modulate ligand–GPCR interactions allosterically. These findings on ion‐mediated GPCR signaling open new vistas for understanding the functioning of GPCRs and further could help in designing potent therapeutic compounds targeting GPCRs. Here we report on recent findings about role of orthosteric and allosteric metal ions in GPCR signaling and drug discovery. This article is categorized under: Structure and Mechanism > Molecular Structures Molecular and Statistical Mechanics > Molecular Mechanics Molecular and Statistical Mechanics > Molecular Interactions
Allosteric sodium ion and its importance for drug discovery. Left: the representative high‐resolution structure of A2AR (PDB: 4EIY) comprising an allosteric Na+ (small blue sphere) next to the highly conserved D2.50. Three water molecules (small red spheres) were also found coordinating with Na+. The antagonist is depicted as yellow balls‐and‐sticks. Middle: the agonist acetylcholine can diffuse from the orthosteric site (cyan) into the vicinity of allosteric sodium site (yellow) as discovered by MD simulations. Right: the crystal structure of LTB4 receptor (PDB: 5X33) with a ligand located around the allosteric sodium site
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An allosteric Na+ (right, upper panel) coordinates the agonist molecule with the receptor in D2R as detected by MD simulations. An allosteric sodium ion (right, lower panel) was observed in the original crystal structure of D2R
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Using MD simulations, an orthosteric Mg2+ was proposed in the crystal structure of μ‐OR after refining the “unidentified” electron density map. It coordinates the agonist molecule with the μ‐OR at the orthosteric site
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Orthosteric Ca2+ in melanocortin‐4 receptor (MC4R, PDB: 6W25). The Ca2+ coordinates the antagonist peptide with the MC4R. It stabilizes the inactive state of MC4R substantially
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Molecular and Statistical Mechanics > Molecular Interactions
Molecular and Statistical Mechanics > Molecular Mechanics
Structure and Mechanism > Molecular Structures

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