Tunnel-like region observed as a potential allosteric site in Staphylococcus aureus Glyceraldehyde-3-phosphate dehydrogenase

Arch Biochem Biophys. 2023 Dec 28;752:109875. doi: 10.1016/j.abb.2023.109875. Online ahead of print.ABSTRACTGlyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzing the sixth step of glycolysis has been investigated for allosteric features that might be used as potential target for specific inhibition of Staphylococcus aureus (S.aureus). X-ray structure of bacterial enzyme for which a tunnel-like opening passing through the center previously proposed as an allosteric site has been subjected to six independent 500 ns long Molecular Dynamics simulations. Harmonic bond restraints were employed at key residues to underline the allosteric feature of this region. A noticeable reduction was observed in the mobility of NAD+ binding domains when restrictions were applied. Also, a substantial decrease in cross-correlations between distant Cα fluctuations was detected throughout the structure. Mutual information (MI) analysis revealed a similar decrease in the degree of correspondence in positional fluctuations in all directions everywhere in the receptor. MI between backbone and side-chain torsional variations changed its distribution profile and decreased considerably around the catalytic sites when restraints were employed. Principal component analysis clearly showed that the restrained state sampled a narrower range of conformations than apo state, especially in the first principal mode due to restriction in the conformational flexibility of NAD+ binding domain. Clustering the t...
Source: Archives of Biochemistry and Biophysics - Category: Biochemistry Authors: Source Type: research