TY  - JOUR
AU  - Kondo, Yasushi
AU  - Hatton, Caitlin
AU  - Cheng, Robert
AU  - Trabuco, Matilde
AU  - Glover, Hannah
AU  - Bertrand, Quentin
AU  - Stierli, Fabienne
AU  - Seidel, Hans-Peter
AU  - Mason, Thomas
AU  - Sarma, Sivathmika
AU  - Tellkamp, Friedjof
AU  - Kepa, Michal
AU  - Dworkowski, Florian
AU  - Mehrabi, Pedram
AU  - Hennig, Michael
AU  - Standfuss, Joerg
TI  - Apo‐state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand
JO  - Protein science
VL  - 34
IS  - 7
SN  - 0961-8368
CY  - Hoboken, NJ
PB  - Wiley
M1  - PUBDB-2025-02316
SP  - e70104
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40521617
DO  - DOI:10.1002/pro.70104
UR  - https://bib-pubdb1.desy.de/record/632990
ER  -