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Modular photoswitchable molecular glues for chemo-optogenetic control of protein function in living cells
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-3322-7864
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0001-7930-0134
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2025 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, article id e202416456Article in journal, Editorial material (Refereed) Epub ahead of print
Abstract [en]

Optogenetic systems using photosensitive proteins and chemically induced dimerization/proximity (CID/CIP) approaches enabled by chemical dimerizers (also termed molecular glues), are powerful tools to elucidate the dynamics of biological systems and to dissect complex biological regulatory networks. Here, we report a versatile chemo-optogenetic system using modular, photoswitchable molecular glues (sMGs) that can undergo repeated cycles of optical control to switch protein function on and off. We use molecular dynamics (MD) simulations to rationally design the sMGs and further expand their scope by incorporating different photoswitches, resulting in sMGs with customizable properties. We demonstrate that this system can be used to reversibly control protein localization, organelle positioning, protein-fragment complementation as well as posttranslational protein levels by light with high spatiotemporal precision. This system enables sophisticated optical manipulation of cellular processes and thus opens up a new avenue for chemo-optogenetics.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2025. article id e202416456
Keywords [en]
Chemically induced dimerization, Chemo-optogenetics, Molecular glue, Photoswitch, Protein degradation
National Category
Biochemistry
Research subject
biological chemistry
Identifiers
URN: urn:nbn:se:umu:diva-235004DOI: 10.1002/anie.202416456ISI: 001417842800010PubMedID: 39777946Scopus ID: 2-s2.0-85215506042OAI: oai:DiVA.org:umu-235004DiVA, id: diva2:1934596
Funder
Swedish Research Council, 2018-0458Swedish Research Council, 2022-0293Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2025-02-04 Created: 2025-02-04 Last updated: 2025-04-24

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Zhang, JunHerzog, Laura K.Corkery, Dale P.Xin, XiaoyiLi, YaozongWu, Yao-Wen

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Zhang, JunHerzog, Laura K.Corkery, Dale P.Xin, XiaoyiLi, YaozongWu, Yao-Wen
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