9HC0

Dark structure of the human metabotropic glutamate receptor 5 transmembrane domain bound to photoswitchable ligand alloswitch-1

Summary for 9HC0

• Entry DOI: 10.2210/pdb9hc0/pdb
• Descriptor: Metabotropic glutamate receptor 5,Endolysin, OLEIC ACID, 2-chloranyl-~{N}-[2-methoxy-4-[(~{E})-pyridin-2-yldiazenyl]phenyl]benzamide, ... (4 entities in total)
• Functional Keywords: g protein-coupled receptor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 51695.75

Authors

Kondo, Y.,Hatton, C.,Cheng, R.,Trabuco, M.,Glover, H.,Bertrand, Q.,Stierli, F.,Seidel, H.P.,Mason, T.,Sarma, S.,Tellkamp, F.,Kepa, M.,Dworkowski, F.,Mehrabi, P.,Hennig, M.,Standfuss, J. (deposition date: 2024-11-08, release date: 2025-06-25)

Primary citation

Kondo, Y.,Hatton, C.,Cheng, R.,Trabuco, M.,Glover, H.,Bertrand, Q.,Stierli, F.,Seidel, H.P.,Mason, T.,Sarma, S.,Tellkamp, F.,Kepa, M.,Dworkowski, F.,Mehrabi, P.,Hennig, M.,Standfuss, J.
Apo-state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand.
Protein Sci., 34:e70104-e70104, 2025

PubMed 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 transient intermediates. The mGlu5 apo-structure provides molecular insights into the ligand-free allosteric pocket, which can guide the design of new allosteric modulators.

PubMed: 40521617
DOI: 10.1002/pro.70104

Experimental method

X-RAY DIFFRACTION (2.33 Å)