Structure and Function of the Refined C-Terminal Loop in Imidazole Glycerol Phosphate Dehydratase from Different Homologs

• DOI: 10.1021/acs.jafc.1c04282
• Publication Date: 2021-11-15T20:20:24Z
• Authors: Leng Wang; Ruiyuan Liu; Yue Meng; Fang Li; Huizhe Lu
• Keywords: Anti-Infective Agents; 0103 physical sciences; Arabidopsis; Animals; Saccharomyces cerevisiae; 01 natural sciences; Hydro-Lyases

IGPD is an essential metalloenzyme that catalyzes histidine biosynthesis. We found its C-terminus loop region has a vital role in determining enzyme activity but been hardly mentioned before. In this work, we focused on the dynamic feature and function of C-Loop Arabidopsis thaliana Saccharomyces cerevisiae (At_IGPD Sc_IGPD, respectively). Due to high flexibility region, performed total 3.4 μs accelerated molecular dynamics simulation enhance sampling. Inhibitor C348 At-IGPD exhibited instability later stage simulation, while characteristic sequence Sc_IGPD reduced solvent interference significantly restrained interaction mode. For C-Loop-assisted ligand-binding process, proposed "Lock-Lid" model. Meanwhile, dissociated ligand At_IGPD served as probe, metastable pocket was determined at root C-Loop, rationality proved by theoretical verification mutation experiments. This study complemented important structural features provided basis for design selective inhibitors. Considering absence mammals, suggested could be promising germicide target.