Figure 2

Example - inhibition of HPR1 by nitration. This figure is an application example of using PyTMs in the setting of enzyme inhibition. Briefly, the model of hydroxypyruvate reductase 1 from Arabidopsis thaliana was nitrated at three specific Tyrosine residues using PyTMS as described in the implementation section. This enzyme has previously been demonstrated to be nitrated at these residues and thereby functionally inhibited. NIY = Nitrotyrosine. A) An overview of the nitrated enzyme monomer is depicted in secondary structure cartoon representation. Additionally, the locations of (Nitro-)Tyrosine residues have been highlighted in stick representation. The nitro groups in residues 97, 108 and 198 are colored red. The co-factor (NADPH) in stick representation is colored blue. B + C) A close-up view of the co-factor (NADPH) binding site in the enzyme. B: native; C: nitrated. Left: Representation as cartoon with the (nitrated) TYR198. Steric clashes based on vdW overlap are represented by the colored discs. The increasing size and redness of the discs correlate with stronger vdW strain. The native enzyme does not have significant steric clashes. The nitration, however, introduces significant steric clashing with the co-factor and occludes the binding site. Right: identical view as in the left image, but depicted as surface with the extent of the nitration colored red. In conclusion, the denied binding of co-factor, mainly due to nitration at TYR198, is the structural basis for impaired enzyme activity.