Since Meischer's initial discovery of DNA in 1869, researchers have worked to understand the structure and function of this fundamental biological molecule. X-ray crystallography has allowed scientists to examine the structure of DNA and the mechanism of DNA interactions with proteins and small molecules at atomic resolution. Numerous crystal structures of different DNA sequences, structures, and complexes have been solved that show that DNA can take on a variety of different conformations to carry out its biological functions in the cell. Despite this wealth of structural information, many questions remain unanswered. In this two-part study, the principles of x-ray crystallography are applied in an effort to determine the structure of DNA complexes from two different biological pathways. In the first system, the interplay between the NF-κB and IRF families of transcription factors within the innate immune response is explored. The NF-κB p50 homodimer is a member of the NF-κB family that is constitutively expressed in the cell. It is known to bind κB DNA sequences in the nucleus and act as a competitive repressor of κB-driven transcription. Recent studies have described a novel p50 DNA binding mechanism in the nucleus in which p50 binds to G-IRE DNA sequences and represses the transcription of interferon response genes. A high-resolution structural model is needed to better understand this mechanism of transcriptional cross regulation in the nucleus. p50:G-IRE complexes were screened for crystallization and several different forms of single complex co-crystals were obtained and tested for diffraction. All crystals tested produced very little and poor diffraction. Future studies are being developed to carry out biophysical characterization on these complexes. In the second system, we explored the interactions between a series of peptide inhibitors and an intermediate of DNA recombination, the Holliday Junction (HJ). There are a series of steps during recombination including DNA cleavage, strand exchange, and ligation to generate the four-armed DNA structure known as the Holliday junction. HJs are targets for the development of inhibitors that are capable of blocking the resolution of the HJ. Researchers in the Segall Laboratory at SDSU have developed several inhibitors that bind HJs and exhibit potent antibacterial properties. However, the precise chemical mechanism by which these interactions occur is unknown. Multiple crystal forms containing the DNA:inhibitor complex have been crystallized and exhibit diffraction to a resolution of 6-8 Å but exhibit high mosaicity, indicating there is a high amount of disorder within the crystals probably due to heterogeneity in our crystal sample. The presence of the peptide within the crystal has been confirmed by excision assay. Crystals are being optimized for further analysis and experiments are being designed to better understand the heterogeneity within the crystals.