Time-resolved structures of β 2 -adrenergic receptor modulation by a photoswitchable beta-blocker
Year: 2025
Type: preprint
Abstract: G protein-coupled receptors (GPCRs) regulate essential physiological responses and are important drug targets, yet their ligand-induced conformational dynamics remain poorly understood. The β 2 -adrenergic receptor (β 2 AR) is a prominent member of the GPCR family. It regulates bronchial and vascular function and is a significant drug target, particularly in respiratory and smooth muscle-related disorders. We employed time-resolved crystallography at X-ray free-electron lasers (XFELs) to capture the conformational dynamics of β 2 AR bound to photoazolol-1, a beta-blocker derivative developed for photopharmacological applications. Structural snapshots of the receptor bound to trans -photoazolol-1 (pre-photoconversion), a strained intermediate, and the fully photoisomerized cis -photoazolol-1 reveal an intricate interplay between ligand chemistry and receptor plasticity. Isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric pocket, altering interactions with the extracellular loop 2 and transmembrane helices 5 and 6. Supported by functional assays, these structural shifts suggest that photoazolol-1 transitions from an inverse agonist to a neutral antagonist upon photoactivation. Our findings uncover a mechanism of GPCR modulation reminiscent of rhodopsin activation and offer a framework for designing ligands that harness light-driven transitions to achieve spatiotemporal control of receptor function.
Authors: Robin Stipp, Quentin Bertrand, Matilde Trabuco, Anna Duran-Corbera, Maria Tindara Ignazzitto, Hannah Glover, Fabienne Stierli, Juanlo Catena, Melissa Carrillo, Sina Hartmann, Hans-Peter Seidel, Matthias Mulder, Thomas Mason, Yasushi Kondo, Maximillian Wranik, Martin Appleby, Christoph Sager, Raymond Sierra, Gregory Gate, Pamela Schleissner, Xinxin Cheng, Tobias Weinert, Robert Cheng, Sandra Mous, John H. Beale, Michal Kepa, Amadeu Llebaria, Michael Hennig, Xavier Rovira, Joerg Standfuss
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Time-resolved structural biology of G protein signaling systems, High-Repetition Rate X-ray Detector for the Coherent X-ray Imaging Instrument at LCLS, G518378871, G6921840335, Linking time-resolved structures and signal transduction within multi-domain photosensors, Towards dynamic serial crystallography without photoswitches
OpenAlex ID: W4414048649