Conformational Dynamics of the μ-Opioid Receptor Reveal Ligand-Specific Efficacy Modulation

Concetti Chiave

Ligand-specific conformational changes of the μ-opioid receptor (μOR) translate into a broad range of intrinsic efficacies at the transducer level.

Sintesi

The content discusses the molecular understanding of drug action on the μ-opioid receptor (μOR), which is an important target for pain management. Using advanced biophysical techniques, the researchers identified several conformations of the cytoplasmic face of the μOR that interconvert on different timescales. These conformations include a pre-activated conformation capable of G-protein binding and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. The interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than the binding of Gi. The findings provide insights into how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level, which can inform the development of better therapeutics.

Statistiche

The μ-opioid receptor (μOR) is an important target for pain management.
Ligand-specific conformational changes of μOR translate into a broad range of intrinsic efficacies at the transducer level.
The interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than the binding of Gi.

Citazioni

"We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex."
"Interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of Gi."

Approfondimenti chiave tratti da

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor - Nature

by Jiawei Zhao,... alle www.nature.com 04-10-2024

https://www.nature.com/articles/s41586-024-07295-2

Domande più approfondite

How do the identified conformational states of the μOR relate to the receptor's functional selectivity and biased signaling?

The identified conformational states of the μOR play a crucial role in the receptor's functional selectivity and biased signaling. Functional selectivity, also known as ligand bias, refers to the ability of different ligands to stabilize distinct receptor conformations, leading to preferential activation of specific signaling pathways. In the case of the μOR, the conformational dynamics observed indicate that different ligands can induce specific receptor conformations that result in varying efficacies at the transducer level. This means that certain ligands may bias the receptor towards activating specific downstream signaling pathways over others, leading to biased signaling. By understanding the conformational states of the μOR and how they are influenced by ligands, researchers can design ligands that selectively activate desired signaling pathways while avoiding others, thus achieving functional selectivity and biased signaling for therapeutic purposes.

What are the potential implications of the less specific and lower affinity binding of β-arrestin-1 compared to Gi on the development of biased μOR agonists?

The less specific and lower affinity binding of β-arrestin-1 compared to Gi has significant implications for the development of biased μOR agonists. β-arrestin-1 is a key player in the desensitization and internalization of G protein-coupled receptors (GPCRs) like the μOR. The lower affinity and less specific binding of β-arrestin-1 suggest that it may not be as readily recruited to the μOR compared to Gi proteins. This differential recruitment of signaling effectors can lead to biased signaling, where certain ligands preferentially activate G protein-mediated pathways over β-arrestin-mediated pathways or vice versa. By understanding the binding kinetics and affinities of β-arrestin-1 and Gi to the μOR, researchers can design biased agonists that selectively target one pathway over the other, potentially leading to improved therapeutic outcomes with reduced side effects.

What other receptor systems could benefit from a similar conformational dynamics analysis to understand ligand-specific efficacy modulation?

Several other receptor systems could benefit from a similar conformational dynamics analysis to understand ligand-specific efficacy modulation. One prominent example is the adrenergic receptor system, which includes α- and β-adrenergic receptors that play crucial roles in regulating cardiovascular function, among other physiological processes. By studying the conformational dynamics of adrenergic receptors in response to different ligands, researchers can uncover how specific ligands induce distinct receptor conformations that lead to biased signaling and functional selectivity. This knowledge can aid in the development of adrenergic receptor ligands with improved therapeutic profiles and reduced side effects. Additionally, other GPCRs such as dopamine receptors, serotonin receptors, and histamine receptors could also benefit from similar conformational dynamics analyses to elucidate ligand-specific efficacy modulation and biased signaling mechanisms for drug development.