Journal Article

PUBDB-2025-02316

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Apo‐state structure of the metabotropic glutamate receptor 5 transmembrane domain obtained using a photoswitchable ligand

Kondo, Y. (Corresponding author)Extern*EMBL* ; 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. (Corresponding author)Extern*XFEL.EU*

2025
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/pro.70104  doi:10.3204/PUBDB-2025-02316

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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)451079909 - Untersuchung allosterischer Mechanismen durch zeitaufgelöste serielle Synchrotronkristallographie (451079909) (451079909)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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