Dihydrofolate reductase is an enzyme that catalyzes the reaction of dihydrofolate to tetrahydrofolate with nicotinamide adenine dinucleotide phosphate. Haloferax volcanii is a “salt-loving” microorganism found in the Dead Sea. Such microorganisms have adapted to their extreme environments and now require extremely high salt concentrations to survive. The study of dihydrofolate reductase from Haloferax volcanii with the substrate folate bound, which is the focus of the work presented in this dissertation, offers further understanding of this adaptation. The effect that high salt concentration has on this enzyme is not fully understood; however, this dissertation includes the investigation of the structure of a halophilic enzyme with substrate bound, providing new information in this uncertain field of research. In particular, the results shown here (along with future studies) can be applied towards the question of how an extremely salty environment affects enzyme function, stability, solubility, and flexibility.Triple resonance nuclear magnetic resonance spectra of the 17.9 kDa enzyme with bound substrate have been interpreted. 1H, 13C, and 15N backbone and side chain chemical shifts were specifically assigned to the amino acids that make up the enzyme. These assignments revealed overall similarities to the chemical shifts of the apo enzyme, with some exceptions. These exceptions are of particular interest as they are due to the binding of folate. Secondary structural analysis of the nuclear magnetic resonance data based on the chemical shift index showed that the binary complex has similar secondary structural features to the folate-bound dihydrofolate reductase from mesophilic Escherichia coli.The structure of dihydrofolate reductase from Haloferax volcanii with folate bound has been investigated using Crystallography and nuclear magnetic resonance system structure calculations, suggesting an overall similarity to the X-ray crystallography and nuclear magnetic resonance structures of apo dihydrofolate reductase from Haloferax volcanii. The results of the structure calculation and secondary structural analysis of the chemical shift assignments suggest secondary structural features including a beta-sheet in the core of the enzyme composed of 8 beta-strands, surrounded by 4 alpha-helices, and 4 major loops. The structure of the binary complex was compared to its mesophilic counterpart, the folate-bound dihydrofolate reductase from Escherichia coli, which was investigated by X-ray crystallography. The results of the work described in this dissertation do not agree with loop structure of the mesophilic complex.