Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding.

ABSTRACT: Inosine 5'-monophosphate dehydrogenase (IMPDH) is a promising antibiotic target. This enzyme catalyzes the NAD-dependent oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP), which is the rate-limiting step in guanine nucleotide biosynthesis. Bacterial IMPDH-specific inhibitors have been developed that bind to the NAD⁺ site. These inhibitors display varied affinities to different bacterial IMPDHs that are not easily rationalized by X-ray crystal structures of enzyme-inhibitor complexes. Inspection of X-ray crystal structures of 25 enzyme-inhibitor complexes, including 10 newly described, suggested that a mobile active site flap may be a structural determinant of inhibitor potency. Saturation transfer difference NMR experiments also suggested that the

SUBMITTER: Wang X 

PROVIDER: S-EPMC11841048 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature