9RPY

Fragment screening of FosAKP, cryo structure in complex with fragment F2X-entry B07

9RPY の概要

• エントリーDOI: 10.2210/pdb9rpy/pdb
• 分子名称: FosA family fosfomycin resistance glutathione transferase, N-[3-(diethylamino)phenyl]ethanamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: antibiotic resistance, fosfomycin, fragment screening, transferase
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33075.06

構造登録者

Guenther, S.,Galchenkova, M.,Fischer, P.,Reinke, P.Y.A.,Falke, S.,Thekku Veedu, S.,Rodrigues, A.C.,Senst, J.,Meents, A. (登録日: 2025-06-25, 公開日: 2025-10-15, 最終更新日: 2025-10-22)

主引用文献

Gunther, S.,Fischer, P.,Galchenkova, M.,Falke, S.,Reinke, P.Y.A.,Thekku Veedu, S.,Rodrigues, A.C.,Senst, J.,Elinjikkal, D.,Gumprecht, L.,Meyer, J.,Chapman, H.N.,Barthelmess, M.,Meents, A.
Room-temperature X-ray fragment screening with serial crystallography.
Nat Commun, 16:9089-9089, 2025

PubMed 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.

PubMed: 41083451
DOI: 10.1038/s41467-025-64918-6

実験手法

X-RAY DIFFRACTION (1.16 Å)