Mechanism of β2AR regulation by an intracellular positive allosteric modulator
Science, 2019•science.org
Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the
most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less
well-defined, and so less exploited clinically. We report the crystal structure of the prototypic
β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a
positive allosteric modulator of this receptor. It binds on the receptor's inner surface in a
pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the …
most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less
well-defined, and so less exploited clinically. We report the crystal structure of the prototypic
β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a
positive allosteric modulator of this receptor. It binds on the receptor's inner surface in a
pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the …
Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2- over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
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