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@ARTICLE{Guenther:637447,
author = {Guenther, Sebastian and Fischer, Pontus and Galchenkova,
Marina and Falke, Sven and Reinke, Patrick and Thekku Veedu,
Sreevidya and Rodrigues, Ana Carolina and Senst, Johanna
Maria and Elinjikkal, Daniel and Gumprecht, Lars and Meyer,
Jan and Chapman, Henry N. and Barthelmess, Miriam and
Meents, Alke},
title = {{R}oom-temperature {X}-ray fragment screening with serial
crystallography},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {PUBDB-2025-03854},
pages = {9089},
year = {2025},
note = {The following grants are not listed in the system and,
therefore, I could not select them:- Federal Ministry of
Education and Research (BMBF) via the
Röntgen-Ångström-Cluster project “X-ray drug design
platform” (13K22CHB) and project “conSCIENCE”
(16GW0277)- Helmholtz Society: FISVIR and SFragX - Helmholtz
Association Impulse and Networking funds
InternLabs-0011-HIR3X- Deutsche Forschungsgemeinschaft
(DFG): Cluster of Excellence “CUI: Advanced Imaging of
Matter” of the—EXC 2056—project ID 390715994},
abstract = {Structural insights into protein-ligand interactions are
essential for advancing drug development, with
macromolecular X-ray crystallography being a cornerstone
technique. Commonly X-ray data collection is conducted at
cryogenic temperatures to mitigate radiation damage effects.
However, this can introduce artifacts not only in the
protein conformation but also in protein-ligand
interactions. Recent studies highlight the advantages of
room-temperature (RT) crystallography in capturing relevant
states much closer to physiological temperatures. We have
advanced fixed-target serial crystallography to enable
high-throughput fragment screening at RT. Here we
systematically compare RT fragment screening with
conventional single crystal data collection at cryogenic
temperature (cryo) of the Fosfomycin-resistance protein A
from Klebsiella pneumoniae (FosAKP), an enzyme involved in
antibiotic resistance. With RT serial crystallography we
achieve resolutions comparable to cryogenic methods and
identify a previously unobserved conformational state of the
active site, offering additional starting points for drug
design. For ligands identified in both screens, temperature
did not have an influence on the binding mode of the ligand.
But overall, we observed more binders at cryo, both at
physiologically relevant and non-relevant sites. With the
potential for further automation, RT screening with serial
crystallography can advance drug development pipelines by
making new conformations of proteins accessible.},
cin = {FS-CFEL-1-BMX},
ddc = {500},
cid = {I:(DE-H253)FS-CFEL-1-BMX-20210408},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633) / 6G3 - PETRA III (DESY) (POF4-6G3)
/ FS-Proposal: BAG-20230011 (BAG-20230011) / FISCOV - FISCOV
Helmholtz large research infrastructures in the fight
against epidemic outbreaks (FISCOV) / AIM, DFG project
G:(GEPRIS)390715994 - EXC 2056: CUI: Advanced Imaging of
Matter (390715994)},
pid = {G:(DE-HGF)POF4-633 / G:(DE-HGF)POF4-6G3 /
G:(DE-H253)BAG-20230011 / G:(DE-HGF)FISCOV /
G:(GEPRIS)390715994},
experiment = {EXP:(DE-H253)P-P09-BMX-20230101 /
EXP:(DE-H253)P-P11-20150101},
typ = {PUB:(DE-HGF)16},
doi = {10.1038/s41467-025-64918-6},
url = {https://bib-pubdb1.desy.de/record/637447},
}