1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
The rational design of stabilizing mutation in IMPDH1 by molecular dynamics simulations: a structural study
Paper ID : 1104-ICB10
Authors:
samira sattari *1, Razieh Yazdanparast2
1University of Tehran
2گروه بیوشیمی- مرکز تحقیقات بیوشیمی و بیوفیزیک-دانشگاه تهران-تهران-ایران
Abstract:
Regulation of purine concentrations is essential for cell growth and proliferation and any imbalance will lead to diseases such as Retinitis Pigmentosa (RP). Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the GTP biosynthesis pathway. Regulation of IMPDH activity is by the CBS domain with a role in the self-assembly of the enzyme in the form of filaments. ATP increases filament formation and enzyme activity, while, GTP inhibits the enzyme via compression and stabilization. Thus, the main goal in this study was to inhibit the enzyme via creating stabilizing mutations in the ATP binding site. Based on the computational approach, an I157V mutation was expected to lead to the enzyme stabilization and inhibition due to both CBS intrinsically disordered conformation and the impaired ATP binding site. The effect of rational design of point mutation was validated by CD spectroscopy, intrinsic and extrinsic fluorescence, and thermal denaturation analysis. Overall, we suggest that I157 mutation to V157 is an important target in drug design for RP disease by increasing enzyme stability, reducing dynamics required for activity, and thus the enzyme inhibition.
Keywords:
IMPDH, Retinitis pigmentosa, Stabilizing mutations, Molecular dynamics
Status : Paper Accepted (Poster Presentation)