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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.

Ligand  pIC50  Zn Arg-291B His-248B Tyr-361B Tyr-300B Lys-294B Lys-164A Ser-357B Arg-202B Lys-356B Asp-359B His-362B
(S)-FPOH 7.52   + +   + +            
ZARA 7.92 +     +     + +        
DESME 4.68 +     +   +     + +    
FUSID 6.52 + + +   +              
BZA-2B 9.07 + + + +             + +
SCH-44342 6.60   + + + +              

ZARA = zaragozic acid, DESME = 10'-desmethoxystreptonigrin, FUSID = fusidienol


Table 2 - Main interactions of FTase - H-RAS-1 - FPP complex.

Substrate Zn Arg-291B His-248B Lys-294B Tyr-300B Lys-164A Trp-106B Ser-357B Tyr-361B
FPP + + + + + +      
H-RAS-1 CVLS +         + + + +