Apo-state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand.

ABSTRACT: 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 transien

SUBMITTER: Kondo Y 

PROVIDER: S-EPMC12168131 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature