Insights on the conformation and appropriate drug-target sites on retinal IMPDH1 using the 604-aa isoform lacking the C-terminal extension.

Background and purpose: Retinitis pigmentosa (RP) accounts for 2 percent of global cases of blindness. The RP10 form of the disease results from mutations in isoform 1 of inosine 5'-monophosphate dehydrogenase (IMPDH1), the rate-limiting enzyme in the Experimental approach: A recombinant 604-aa IMPDH1 isoform lacking the carboxyl-terminal peptide was produced and underwent proteolytic digestion with α-chymotrypsin. Dimer models of wild type and engineered 604-aa isoform were subjected to molecular dynamics simulation. Findings/Results: The IMPDH1 retinal isoform lacking C-terminal peptide was shown to tend to have more rapid proteolysis (~16% digestion in the first two minutes). Our computational data predicted the potential of the amino-terminal peptide to induce spontaneous inhibition of IMPDH1 by forming a novel helix in a GTP binding site. On the other hand, the C-terminal peptide might block the probable inhibitory role of the N-terminal extension. Conclusion and implications: According to the findings, augmenting IMPDH1 activity by suppressing its filamentation is suggested as a suitable strategy to compensate for its disrupted activity in RP. This needs specific small molecule inhibitors to target the filament assembly interface of the enzyme.