X-Ray Crystal Structure of an Iridium Complex Bound to a DNA G-Quadruplex
Associated Gleghorn Lab Researchers
Iridium is a non-toxic heavy metal element currently used in cancer research. When bonded to specific organic molecules, the resulting cyclometalated complex may exhibit bioluminescence, and bind to guanine-rich G-quadruplex (G4) structures in telomeric or oncogenic regions of DNA. Successful binding has potential to biomark cancer cells and discover the role G4s play in cancer development.
Left: G4 crystals soaked with the iridium-containing ligand. Dissolved ligand appears as the orange tint, which is the color of the compound in its solid form.
The immediate goal of this research is to find the crystal binding conditions for the cyclometalated iridium(III) ligand given to us by our collaborator (Dr. Carly Reed, SUNY Brockport) that permits G4 interaction, and then produce a crystal structure of the full complex.
Left and Below: Structures of an example G4, from Protein Data Bank (PDB) ID 6AU4. Guanine-rich DNA strands associate with themselves to form quadruplex structures like this through Hoogsteen hydrogen bonding and pi stacking.
In this G4, potassium ions line the center, as found by X-ray diffraction data. Guanine bases are represented in green, and the sequence is from the major G4 formed in the promoter region of the human c-MYC oncogene.
These images were obtained using UCSF ChimeraX.
Native and ligand-soaked crystals were collected. These crystals were analyzed via X-ray diffraction at Brookhaven National Laboratory using their National Synchrotron Light Source II (NSLS II). Electron density data was analyzed but the presence of ligand was not found in any of the structures that were phased and preliminarily modeled.
Left: Various X-ray diffraction datasets. Larger ligand soaks resulted in larger unit cells and disrupted the G4 as shown, but no density for the ligand was found.
Image 1: Soaked model with no electron density shown, showing the disrupted G4 in the asymmetric unit.
Image 2: Image 1 with electron density data added
Image 3: Soaked model with a lower concentration ligand soak
Work is underway to determine new crystal conditions in order to conduct a new round of X-ray diffraction experiments towards determining this crystal structure. This work will aid in the understanding of G4 DNA dynamics and add to a growing database of G4-ligand structures to aid in biomarking of in vivo G4s.
Dr. Michael L. Gleghorn and the Gleghorn Research Lab at RIT, Dr. Carly Reed (SUNY Brockport), RIT College of Science, RIT Emerson Summer Undergraduate Research Fellowships (SURF), Hauptman-Woodward Medical Research Institute, Brookhaven National Laboratory, Dr. Jean Jakoncic