Apo‐state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand
Metabotropic glutamate receptor 5 (mGlu5) is implicated in various neurodegenerative disorders, making it an attractive drug target. Although several ligand-bound crystal structures of mGlu5 exist, their apo-state crystal structure remains unknown. Here, we study mGlu5 structural changes using the photochemical affinity switch, alloswitch-1, in combination with time-resolved freeze-trapping methods. By X-ray crystallography, we demonstrated that isomerizing alloswitch-1 leads to its release from the binding pocket within a few seconds. The apo structure, determined at a resolution of 2.9 Å, is more comparable to the inactive state than to the active state. Our approach presents an accessible alternative to time-resolved serial crystallography for capturing thermodynamically stable transient intermediates. The mGlu5 apo-structure provides molecular insights into the ligand-free allosteric pocket, which can guide the design of new allosteric modulators.
Authors
- Caitlin E. Hatton (ORCID: https://orcid.org/0000-0002-8446-0711)
- J. Standfuss (ORCID: https://orcid.org/0000-0001-8825-386X)
- Michal Kepa (ORCID: https://orcid.org/0000-0002-4045-3990)
- Hannah Glover (ORCID: https://orcid.org/0000-0001-6558-8878)
- Michael Hennig (ORCID: https://orcid.org/0000-0002-1839-2351)
- Friedjof Tellkamp (ORCID: https://orcid.org/0000-0002-5670-3544)
- P. Mehrabi (ORCID: https://orcid.org/0000-0003-3211-6959)
- Matilde Trabuco (ORCID: https://orcid.org/0000-0001-9234-8685)
- Quentin Bertrand (ORCID: https://orcid.org/0000-0003-3476-1775)
- Fabienne Stierli
- Yasushi Kondo (ORCID: https://orcid.org/0000-0003-2131-575X)
- H. Martin Seidel
- R.K. Cheng (ORCID: https://orcid.org/0000-0001-7564-1230)
- Florian Dworkowski (ORCID: https://orcid.org/0000-0001-5004-8684)
- Siddhartha P. Sarma (ORCID: https://orcid.org/0000-0001-7619-8904)
- Thomas J. Mason (ORCID: https://orcid.org/0009-0002-7823-6497)
Institutions
- Laboratoire de physique des Solides (FR)
- Paul Scherrer Institute (CH)
- Biotech Park (IN)
- Max Planck Institute for the Structure and Dynamics of Matter (DE)
Publication Details
- Journal
- Protein Science
- Published
- 2025-06-16
- DOI
- https://doi.org/10.1002/pro.70104
- Citations
- 4
- Primary Topic
- Photochromic and Fluorescence Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 2.07
Funders
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung