Room-temperature X-ray fragment screening with serial crystallography

Sebastian Günther (), Pontus Fischer, Marina Galchenkova, Sven Falke, Patrick Y. A. Reinke, Sreevidya Thekku Veedu, Ana Carolina Rodrigues, Johanna Senst, Daniel Elinjikkal, Lars Gumprecht, Jan Meyer, Henry N. Chapman, Miriam Barthelmess and Alke Meents ()
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Sebastian Günther: Deutsches Elektronen-Synchrotron DESY
Pontus Fischer: Deutsches Elektronen-Synchrotron DESY
Marina Galchenkova: Deutsches Elektronen-Synchrotron DESY
Sven Falke: Deutsches Elektronen-Synchrotron DESY
Patrick Y. A. Reinke: Deutsches Elektronen-Synchrotron DESY
Sreevidya Thekku Veedu: Deutsches Elektronen-Synchrotron DESY
Ana Carolina Rodrigues: Deutsches Elektronen-Synchrotron DESY
Johanna Senst: Deutsches Elektronen-Synchrotron DESY
Daniel Elinjikkal: Deutsches Elektronen-Synchrotron DESY
Lars Gumprecht: Deutsches Elektronen-Synchrotron DESY
Jan Meyer: Deutsches Elektronen-Synchrotron DESY
Henry N. Chapman: Deutsches Elektronen-Synchrotron DESY
Miriam Barthelmess: Deutsches Elektronen-Synchrotron DESY
Alke Meents: Deutsches Elektronen-Synchrotron DESY

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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 of the Fosfomycin-resistance protein A from Klebsiella pneumoniae (FosAKP), an enzyme involved in antibiotic resistance, with conventional single crystal data collection at cryogenic temperature (cryo). 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 does not have an influence on the binding mode of the ligand. But overall, we observe 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 undiscovered conformations of proteins accessible.

Date: 2025
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DOI: 10.1038/s41467-025-64918-6

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