Samira Sattari - Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
Razieh Yazdanparast - Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran

Regulation of purine concentrations is essential for cell growth and proliferation and any imbalance will leadto diseases such as Retinitis Pigmentosa (RP). Inosine monophosphate dehydrogenase (IMPDH) catalyzesthe rate-limiting step in the GTP biosynthesis pathway. Regulation of IMPDH activity is by the CBS domainwith a role in the self-assembly of the enzyme in the form of filaments. ATP increases filament formationand enzyme activity, while GTP inhibits the enzyme via compression and stabilization. Thus, the main goalin this study was to inhibit the enzyme via creating stabilizing mutations in the ATP binding site. Based onthe computational approach, an I۱۵۷V mutation was expected to lead to the enzyme stabilization andinhibition due to both CBS intrinsically disordered conformation and the impaired ATP binding site. Theeffect of rational design of point mutation was validated by CD spectroscopy, intrinsic and extrinsicfluorescence, and thermal denaturation analysis. Overall, we suggest that I۱۵۷ mutation to V۱۵۷ is animportant target in drug design for RP disease by increasing enzyme stability, reducing dynamics requiredfor activity, and thus the enzyme inhibition.

IMPDH, Retinitis pigmentosa, Stabilizing mutations, Molecular dynamics