Dynamic Interactions in the Human β1AR Signalling Complex with Mini-Gs Revealed by NMR
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Date
2025-12-01
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Journal Article
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yes
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Abstract
A wealth of insights into the mechanisms of GPCRs have been gained from biophysical studies of thermostabilized β1 adrenergic receptors (β1AR) from turkey. Here we investigate a stabilised variant of the pharmacologically more relevant human β1AR and present initial insights into the active signalling complex with the G protein surrogate mini-Gs. Compared to the avian receptor, the human β1AR construct exhibits greater conformational flexibility and more readily transitions between inactive and pre-active states; however, the transition to the fully active, open state remains slow. Interestingly, in contrast, the bound mini-Gs protein exhibits much faster dynamics in the ternary complex. For the receptor in the signalling complex, we reveal at least two interconverting states of intracellular loop 2 and the extracellular end of transmembrane helix 1. Additionally, we demonstrate that intracellular loop 3 contributes to mini-Gs binding. This human β1AR construct provides a valuable platform for biophysical studies at the atomic level towards understanding the behaviour of the human receptor.
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published
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437 (23)
Pages / Article No.
169411
Publisher
Elsevier
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Subject
GPCR; signalling complex; human beta 1 adrenergic receptor; NMR; dynamics
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Funding
179319 - NMR studies of the activation states and dynamics of ternary complexes of ß-adrenergic receptors with their ligands and effectors (SNF)
208029 - Dynamics and interactions of GPCRs and GRKs studied by NMR at atomic level. (SNF)
208029 - Dynamics and interactions of GPCRs and GRKs studied by NMR at atomic level. (SNF)