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@ARTICLE{Kondo:632990,
author = {Kondo, Yasushi and Hatton, Caitlin and Cheng, Robert and
Trabuco, Matilde and Glover, Hannah and Bertrand, Quentin
and Stierli, Fabienne and Seidel, Hans-Peter and Mason,
Thomas and Sarma, Sivathmika and Tellkamp, Friedjof and
Kepa, Michal and Dworkowski, Florian and Mehrabi, Pedram and
Hennig, Michael and Standfuss, Joerg},
title = {{A}po‐state structure of the metabotropic glutamate
receptor 5 transmembrane domain obtained using a
photoswitchable ligand},
journal = {Protein science},
volume = {34},
number = {7},
issn = {0961-8368},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {PUBDB-2025-02316},
pages = {e70104},
year = {2025},
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.},
cin = {EMBL-User},
ddc = {610},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3) / DFG project
G:(GEPRIS)451079909 - Untersuchung allosterischer
Mechanismen durch zeitaufgelöste serielle
Synchrotronkristallographie (451079909)},
pid = {G:(DE-HGF)POF4-6G3 / G:(GEPRIS)451079909},
experiment = {EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40521617},
doi = {10.1002/pro.70104},
url = {https://bib-pubdb1.desy.de/record/632990},
}