Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor

Bharat Poudel, Rajitha Rajeshwar T and Juan M. Vanegas ()
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Bharat Poudel: The University of Vermont
Rajitha Rajeshwar T: The University of Vermont
Juan M. Vanegas: The University of Vermont

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract The Angiotensin II Type 1 (AT1) receptor is one of the most widely studied GPCRs within the context of biased signaling. While the AT1 receptor is activated by agonists such as the peptide AngII, it can also be activated by mechanical stimuli such as membrane stretch or shear in the absence of a ligand. Despite the importance of mechanical activation of the AT1 receptor in biological processes such as vasoconstriction, little is known about the structural changes induced by external physical stimuli mediated by the surrounding lipid membrane. Here, we present a systematic simulation study that characterizes the activation of the AT1 receptor under various membrane environments and mechanical stimuli. We show that stability of the active state is highly sensitive to membrane thickness and tension. Structural comparison of membrane-mediated vs. agonist-induced activation shows that the AT1 receptor has distinct active conformations. This is supported by multi-microsecond free energy calculations that show unique landscapes for the inactive and various active states. Our modeling results provide structural insights into the mechanical activation of the AT1 receptor and how it may produce different functional outcomes within the framework of biased agonism.

Date: 2023
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DOI: 10.1038/s41467-023-40433-4

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