LAUSR

Significance β2ARs are the primary targets for relieving bronchoconstriction in airway diseases such as asthma and COPD. Activation of airway smooth muscle (ASM) β2ARs promotes therapeutic effects (via β2AR-Gs pathway) that are constrained by β2AR engagement with the regulatory protein β-arrestin. Moreover, chronic activation of β2AR promotes agonist-specific desensitization that contributes to a loss of β2AR function and the diminished effectiveness of β-agonists in managing asthma. Using computational approaches, we identified an allosteric site on an intermediate conformation of β2AR and associated positive modulators that augmented: 1) beneficial signaling mediated via the canonical β2AR-Gs pathway; 2) relaxation of ASM cells; and 3) dilation of airways ex vivo induced by β-agonists, outcomes that promote therapeutic effects of β-agonists in obstructive lung diseases.