Seungkirl Ahn

Manifold roles of β-arrestins in GPCR signaling elucidated with siRNA and CRISPR/Cas9

Science Signaling · 2018-09-25 · 212 citations

AR-mediated stimulation of ERK1/2 to become more dependent on G proteins, which was reversed by reintroducing βArr1/2. These data suggest that βArr1/2 function as a regulatory hub, determining the balance between mechanistically different pathways that result in activation of ERK1/2, and caution against extrapolating results obtained from βArr1/2- or G protein-deleted cells to GPCR behavior in native systems.

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Nature · 2017-08-01 · 206 citations

Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library

Proceedings of the National Academy of Sciences · 2017-01-27 · 164 citations

Significance The present study reports the discovery of a small-molecule negative allosteric modulator for the β 2 -adrenergic receptor (β 2 AR) via in vitro affinity-based iterative selection of highly diverse DNA-encoded small-molecule libraries. Characterization of the compound demonstrates its selectivity for the β 2 AR and that it negatively modulates a wide range of receptor functions. More importantly, our findings establish a generally applicable, proof-of-concept strategy for screening…

Mechanism of β ₂ AR regulation by an intracellular positive allosteric modulator

Science · 2019-06-27 · 132 citations

Positive reinforcement in a GPCR Many drug discovery efforts focus on G protein–coupled receptors (GPCRs), a class of receptors that regulate many physiological processes. An exemplar is the β 2 -adrenergic receptor (β 2 AR), which is targeted by both blockers and agonists to treat cardiovascular and respiratory diseases. Most GPCR drugs target the primary (orthosteric) ligand binding site, but binding at allosteric sites can modulate activation. Because such allosteric sites are less conserved,…

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries

Molecular Pharmacology · 2018-05-16 · 92 citations

Conventional drug discovery efforts at the <i>β</i>₂-adrenoceptor (<i>β</i>₂AR) have led to the development of ligands that bind almost exclusively to the receptor’s hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein–coupled receptors (GPCRs) with D…