Intracellular Pocket Conformations Determine Signaling Efficacy through the μ Opioid Receptor
David A. Cooper, Joseph DePaolo-Boisvert, Stanley A. Nicholson, Barien Gad, David D. L. Minh
TL;DR
The study shows that the shape of receptor pockets determines how strongly a drug activates cell signals through the μ opioid receptor.
Contribution
A machine learning model is introduced that calculates signaling efficacy based on intracellular pocket conformations.
Findings
Signaling efficacy is linearly proportional to the probability of intracellular pocket conformations.
The model accurately computes G protein and β-arrestin-2 signaling efficacy.
Intracellular pocket expansion and sodium binding pocket collapse are linked to receptor activation.
Abstract
It has been challenging to determine how a ligand that binds to a receptor activates downstream signaling pathways and to predict the strength of signaling. The challenge is compounded by functional selectivity, in which a single ligand binding to a single receptor can activate multiple signaling pathways at different levels. Spectroscopic studies show that in the largest class of cell surface receptors, 7 transmembrane receptors (7TMRs), activation is associated with ligand-induced shifts in the equilibria of intracellular pocket conformations in the absence of transducer proteins. We hypothesized that signaling through the μ opioid receptor, a prototypical 7TMR, is linearly proportional to the equilibrium probability of observing intracellular pocket conformations in the receptor–ligand complex. Here, we show that a machine learning model based on this hypothesis accurately calculates…
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Taxonomy
TopicsReceptor Mechanisms and Signaling · Neuropeptides and Animal Physiology · Pharmacological Receptor Mechanisms and Effects