Model of an organophosphatase-inhibitor complex

An enzyme from bacteria in the soil is able to hydrolyze (and detoxify) powerful nerve toxin, organophosphates. While some of the compounds are effective insecticides, others are anti-personnel toxins, otherwise known as nerve gasses.

The structure of one of these enzymes has been crystallographically determined to 2.1Å resolution1,2. The atomic coordinates of the active site were input to program SCULPT3 and commercial red oak was used to sculpt a model of the active site, scaled to CPK models (1.25 inches = 1Å).

 

 

Figure 1 shows the assembled model (8"x6"x7") of the empty active site (constructed in two parts, each containing 6 slabs of 0.75 inch (1.9cm) thickness)
 
 
 
 

 

 

Figure 2 shows the two sections with a CPK model of the inhibitor=substrate
 

 

 

 

 

 

 

Figure 3 shows the assembled model with the inhibitor docked into the active site of the enzyme. CPK models have been used successfully for 40 years to create realistic scaled images of molecules. They proved to be impractical to use as macromolecular models and were replaced by interactive computer graphics with the advent of the Protein Data Bank4. The creation of a scaled model of an active or ligand binding site makes it possible to use hand-held CPK models to study ligand docking interactions. The educational implications of such models are being explored, along with the obvious implications for structure-based drug design.


 


 
1 Vanhooke, J. L., Benning, M. M., Raushel, F. M., Holden, H. M. (1996):  "Three-dimensional structure of the zinc-containing phosphotriesterase with the bound substrate analog diethyl 4-methylbenzylphosphonate".  Biochemistry 35:6020-6025

Protein Data Bank entry 1DPM

3  E. F. Meyer, S. M. Swanson, & J. A. Williams (2000),"Molecular Modelling & Drug Design"  Pharmacology & Therapeutics  85:113-121

4  E.F. Meyer, (1997) "The First Years of the Protein Data Bank";  Protein Science 6:1591-1597

January-February, 2000

E. Meyer fecit