9RKI
Mixed model refinement of beta-2 Adrenergic receptor with photoazolol in dark state and Light state, 17 nanoseconds after light activation, recorded at LCLS
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Summary for 9RKI
| Entry DOI | 10.2210/pdb9rki/pdb |
| Descriptor | Beta-2 adrenergic receptor,Endolysin, PENTAETHYLENE GLYCOL, ~{N}-[4-[(~{E})-[2-[(2~{S})-2-oxidanyl-3-(propan-2-ylamino)propoxy]phenyl]diazenyl]phenyl]ethanamide, ... (12 entities in total) |
| Functional Keywords | gpcr, 7tm, beta 2, adrenergic, lipidic cubic phase, lipidic, membrane protein, photo-switchable compounds, photoazolol-1, time resolve crystallography |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 57579.63 |
| Authors | Bertrand, Q.,Stipp, R.,Glover, H.,Stierli, F.,Siedel, H.P.,Mous, S.,Kepa, M.,Weinert, T.,Standfuss, J. (deposition date: 2025-06-13, release date: 2026-04-22, Last modification date: 2026-05-06) |
| Primary citation | Stipp, R.,Bertrand, Q.,Trabuco, M.,Duran-Corbera, A.,Ignazzitto, M.T.,Glover, H.,Stierli, F.,Catena, J.,Carrillo, M.,Hartmann, S.,Seidel, H.P.,Mulder, M.,Mason, T.,Kondo, Y.,Wranik, M.,Appleby, M.,Sager, C.,Sierra, R.,Gate, G.,Schleissner, P.,Cheng, X.,Weinert, T.,Cheng, R.,Mous, S.,Beale, J.H.,Kepa, M.,Llebaria, A.,Hennig, M.,Rovira, X.,Standfuss, J. Structural Mechanism of an Efficacy Photoswitch Targeting the beta 2 -adrenergic Receptor. Angew.Chem.Int.Ed.Engl., 65:e17995-e17995, 2026 Cited by PubMed Abstract: The field of photopharmacology develops light-responsive drugs that can modulate protein activity, enabling precise and dynamic investigations of their roles in health and disease. Adrenergic receptors are prominent targets for this approach because they are prototypical G protein-coupled receptors with high clinical relevance in bronchial and cardiovascular diseases. Here, we employed the azobenzene-based compound photoazolol-1 in combination with time-resolved serial crystallography at X-ray free-electron lasers to resolve the molecular mechanisms by which photoswitchable β-blockers modulate activity of the β-adrenoceptor (βAR). Time-resolved structures of the receptor bound to trans-photoazolol-1 (pre-photoconversion), a strained intermediate in the nanosecond range, and the fully photoisomerized cis-photoazolol-1 reveal how isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric ligand binding pocket. Within seconds, light-excited photoazolol-1 adopts a new binding pose, altering interactions with extracellular loop 2 and shifting the positions of transmembrane helices 5, 6, and 7. Functional assays of βAR in cellular membranes show that photoazolol-1 acts as an efficacy photoswitch, changing from an inverse agonist to a neutral antagonist upon isomerization without leaving the binding pocket. In combination, these findings suggest a molecular mechanism for activity modulation via efficacy photoswitches and provide a framework for designing ligands that exploit light-driven transitions within the binding pocket to achieve spatiotemporal control of receptor function. PubMed: 41848496DOI: 10.1002/anie.202517995 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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