Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor
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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2026 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositório: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:dnet:digitalcsic_::e1f097cf1384d5a69e9a14d0ff922059 |
| Acesso em linha: | http://hdl.handle.net/10261/425703 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Time‐resolved serial femtosecond crystallography G protein‐coupled receptors Activity modulation Azobenzene photoswitches Photopharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
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Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| title |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| spellingShingle |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor Stipp, Robin Time‐resolved serial femtosecond crystallography G protein‐coupled receptors Activity modulation Azobenzene photoswitches Photopharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
| title_short |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| title_full |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| title_fullStr |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| title_full_unstemmed |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| title_sort |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor |
| dc.creator.none.fl_str_mv |
Stipp, Robin Bertrand, Quentin Trabuco, Matilde Duran-Corbera, Anna Ignazzitto, Maria Tindara Glover, Hannah Stierli, Fabienne Catena, Juanlo Carrillo, Melissa Hartmann, Sina Seidel, Hans-Peter Mulder, Matthias Mason, Thomas Kondo, Yasushi Wranik, Maximillian Appleby, Martin Sager, Christoph Sierra, Raymond Gate, Gregory Schleissner, Pamela Cheng, Xinxin Weinert, Tobias Cheng, Robert Mous, Sandra Beale, John H. Kepa, Michal Llebaria, Amadeu Hennig, Michael Rovira, Xavier Standfuss, Joerg |
| author |
Stipp, Robin |
| author_facet |
Stipp, Robin Bertrand, Quentin Trabuco, Matilde Duran-Corbera, Anna Ignazzitto, Maria Tindara Glover, Hannah Stierli, Fabienne Catena, Juanlo Carrillo, Melissa Hartmann, Sina Seidel, Hans-Peter Mulder, Matthias Mason, Thomas Kondo, Yasushi Wranik, Maximillian Appleby, Martin Sager, Christoph Sierra, Raymond Gate, Gregory Schleissner, Pamela Cheng, Xinxin Weinert, Tobias Cheng, Robert Mous, Sandra Beale, John H. Kepa, Michal Llebaria, Amadeu Hennig, Michael Rovira, Xavier Standfuss, Joerg |
| author_role |
author |
| author2 |
Bertrand, Quentin Trabuco, Matilde Duran-Corbera, Anna Ignazzitto, Maria Tindara Glover, Hannah Stierli, Fabienne Catena, Juanlo Carrillo, Melissa Hartmann, Sina Seidel, Hans-Peter Mulder, Matthias Mason, Thomas Kondo, Yasushi Wranik, Maximillian Appleby, Martin Sager, Christoph Sierra, Raymond Gate, Gregory Schleissner, Pamela Cheng, Xinxin Weinert, Tobias Cheng, Robert Mous, Sandra Beale, John H. Kepa, Michal Llebaria, Amadeu Hennig, Michael Rovira, Xavier Standfuss, Joerg |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Time‐resolved serial femtosecond crystallography G protein‐coupled receptors Activity modulation Azobenzene photoswitches Photopharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
| topic |
Time‐resolved serial femtosecond crystallography G protein‐coupled receptors Activity modulation Azobenzene photoswitches Photopharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
| description |
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 β2-adrenoceptor (β2AR). 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 β2AR 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. |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 2026 2026 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/425703 |
| url |
http://hdl.handle.net/10261/425703 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Angewandte Chemie (International ed. in English) https://doi.org/10.1002/anie.202517995 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Wiley-VCH |
| publisher.none.fl_str_mv |
Wiley-VCH |
| dc.source.none.fl_str_mv |
reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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| _version_ |
1869422616562892800 |
| spelling |
Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic ReceptorStipp, RobinBertrand, QuentinTrabuco, MatildeDuran-Corbera, AnnaIgnazzitto, Maria TindaraGlover, HannahStierli, FabienneCatena, JuanloCarrillo, MelissaHartmann, SinaSeidel, Hans-PeterMulder, MatthiasMason, ThomasKondo, YasushiWranik, MaximillianAppleby, MartinSager, ChristophSierra, RaymondGate, GregorySchleissner, PamelaCheng, XinxinWeinert, TobiasCheng, RobertMous, SandraBeale, John H.Kepa, MichalLlebaria, AmadeuHennig, MichaelRovira, XavierStandfuss, JoergTime‐resolved serial femtosecond crystallographyG protein‐coupled receptorsActivity modulationAzobenzene photoswitchesPhotopharmacologyhttp://metadata.un.org/sdg/9http://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesBuild resilient infrastructure, promote inclusive and sustainable industrialization and foster innovationThe 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 β2-adrenoceptor (β2AR). 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 β2AR 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.We are grateful for the support from the PSI Crystallization Facility and the Macromolecular Crystallography group during the growing and testing of crystals at the Swiss Light Source. The Biomolecular Structure and Mechanism Program of the Life Science Zürich Graduate School is acknowledged for its academic framework for our graduate students. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. This work was supported by the National Institutes of Health grant S10 OD025079. Beamtime at the Cristallina station of the Swiss X-ray Free Electron laser (SwissFEL) was granted under proposal 20231114 in the first user run. The work was further funded by the Swiss National Science Foundation Project Grants 310030_197674 (to T.W.) and 310030_207462 (J.S.), the Swiss Innovation Agency Innosuisse Grant 42711.1 IP-LS (to M.H. and J.S.), the Swiss National Science Foundation Sinergia Grant CRSII5_213507 (J.S.), the Swiss Nanoscience Institute SNI #1904 (M.C.), the PSI Research Grant (to J.B. and J.S.), the Ministerio de Ciencia e Innovación and Agencia Estatal de Investigación and ERDF—A way of making Europe, PID2020-120499RB-I00 (AL and XR) and RYC2020-029485-I (XR), the Ministerio de Ciencia, Innovación y Universidades, PID2023-152950OB-I00 (AL) and PID2023-151614NB-I00 (XR), the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)—Generalitat de Catalunya, 2021 SGR 00508 (AL) and the Spanish National Research Council, 20228AT014 (XR) Open access publishing facilitated by ETH-Bereich Forschungsanstalten, as part of the Wiley - ETH-Bereich Forschungsanstalten agreement via the Consortium Of Swiss Academic Libraries.Peer reviewedWiley-VCHConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262026info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/425703reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésAngewandte Chemie (International ed. in English)https://doi.org/10.1002/anie.202517995Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::e1f097cf1384d5a69e9a14d0ff9220592026-05-22T06:33:51Z |
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15,812429 |