Table 1 shows the main interactions and the pIC50
for each FTase-inhibitor complex. In Table 2 the
aminoacidic residues involved in the ternary complex
FTase - HRAS-1 - FPP are mentioned.
With the exception of Lys-164A, which represents the
only common interaction point, the residues involved in the
complex formation are different, because the substrates bind at
two distinct. In the (S)-FPOH complex (see
Table 1), the inhibitor is not coordinated with the zinc ion
although the (S)-FPOH is placed at the same site of FPP. The
reason of this behaviour is the presence of the hydroxyl group of
(S)-FPOH; this OH group has an unfavourable effect on the
interaction. With the exception of SCH-44342, the other inhibitors coordinate the zinc.
The inhibitors table (Table 1) shows that Arg-291B, His-248B and Tyr-361B are the main aminoacidic residues involved in the stabilization of the complex. When the orientations of each FTase antagonist and those of the natural ligands are compared, one can observe that the inhibitors studied can be classified into three groups according to the interaction site:
BZA-2B has additional interactions with
aminoacidic groups (Asp-359B and His-362B) that
are not involved in the formation of any of the other complexes,
including the FTase-HRAS-FPP complex. Thus, these results provide
qualitatively acceptable hints for an interpretation of the
different behaviour of ligands vs. the FTase.
Table 1 - Main interactions and pIC50 of FTase-inhibitor complexes.
ZARA = zaragozic acid, DESME = 10'-desmethoxystreptonigrin, FUSID = fusidienol
Table 2 - Main interactions of FTase - H-RAS-1 - FPP complex.