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Although several ligand\u2010bound crystal structures of mGlu5 exist, their apo\u2010state crystal structure remains unknown. Here, we study mGlu5 structural changes using the photochemical affinity switch, alloswitch\u20101, in combination with time\u2010resolved freeze\u2010trapping methods. By X\u2010ray crystallography, we demonstrated that isomerizing alloswitch\u20101 leads to its release from the binding pocket within a few seconds. The apo structure, determined at a resolution of 2.9\u2009\u00c5, is more comparable to the inactive state than to the active state. Our approach presents an accessible alternative to time\u2010resolved serial crystallography for capturing thermodynamically stable transient intermediates. The mGlu5 apo\u2010structure provides molecular insights into the ligand\u2010free allosteric pocket, which can guide the design of new allosteric modulators.<\/jats:p>","DOI":"10.1002\/pro.70104","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T02:15:43Z","timestamp":1750990543000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Apo\u2010state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-575X","authenticated-orcid":false,"given":"Yasushi","family":"Kondo","sequence":"first","affiliation":[{"name":"PSI Center for Life Sciences, Laboratory of Biomolecular Research Paul Scherrer Institute  Villigen PSI 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Scherrer Institute  Villigen PSI Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivathmika","family":"Sarma","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences, Laboratory of Biomolecular Research Paul Scherrer Institute  Villigen PSI Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedjof","family":"Tellkamp","sequence":"additional","affiliation":[{"name":"Max Planck Institute for the Structure and Dynamics of Matter  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kepa","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences, Laboratory of Biomolecular Research Paul Scherrer Institute  Villigen PSI Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Dworkowski","sequence":"additional","affiliation":[{"name":"PSI Center for Photon Science, Laboratory for Synchrotron Radiation and 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