X-ray structure of the human Nijmegen breakage syndrome forkhead-associated/BRCA1 C-terminal domain and computational docking of candidate radiosensitizers.

Nijmegen breakage syndrome 1 (NBS1) forms the MRE11-RAD50-NBS1 complex and is essential for homologous recombination repair of DNA double-strand breaks. NBS1 regulates the localization and activity of the MRN complex. The NBS1 forkhead-associated (FHA) domain represents a potential target for the development of radiosensitizers. However, detailed structural information on the N-terminal region of human NBS1 (hNBS1) is still lacking. Here, the X-ray structure of the hNBS1 FHA-BRCA1 C-terminal (BRCT1)-BRCT2 domains is reported and ligand binding is evaluated using computational docking. A candidate radiosensitizer was predicted to bind at the tip of the FHA domain, indicating a potential interaction site. Substitution of Arg28 with aspartic acid within the FHA domain altered the orientation of neighboring side chains and modified the surface electrostatic properties, supporting its structural and functional importance. These findings provide a structural basis for targeting NBS1 and may facilitate the development of radiosensitizers.