Crystal structure

Abstract

A crystal of pantothenate synthetase (PS) has a monoclinic space group P2 1 and unit cell dimensions of a=66.0±0.2 Å, b=78.1±0.2 Å, c=77.1±0.2 Å and β=103.7±0.2°

What is claimed is:  
     
         1 . A crystal of pantothenate synthetase (PS) having a monoclinic space group P2 1  and unit cell dimensions of a=66.0±0.2 Å, b=78.1±0.2 Å, c=77.1±0.2 Å and β=103.7±0.2°.  
     
     
         2 . A crystal of PS having the three dimensional atomic coordinates of Table 1.  
     
     
         3 . A method for crystallizing a selenium atom PS derivative which comprises producing PS by recombinant production in a bacterial host in the presence of selenomethionine, recovering a selenium atom PS derivative from the host and growing crystals from the recovered selenium atom PS derivative.  
     
     
         4 . A method for identifying a potential inhibitor of PS comprising the steps of: 
 a. employing a three-dimensional structure of PS, or at least one sub-domain thereof, to characterise at least one PS active site, said three-dimensional structure being defined by atomic coordinate data according to Table 1; and    b. identifying said potential inhibitor by designing or selecting a compound for interaction with said active site.    
     
     
         5 . A method according to  claim 4 , wherein step b. involves selecting said compound by computationally screening a database of compounds for interaction with said active site.  
     
     
         6 . A method according to  claim 4 , comprising the further steps of: 
 c. obtaining or synthesising said potential inhibitor; and    d. contacting said potential inhibitor with PS to determine the ability of said potential inhibitor to interact with PS.    
     
     
         7 . A method according to  claim 6 , wherein in step c. said potential inhibitor is contacted with PS in the presence of a substrate to determine the ability of said potential inhibitor to inhibit PS.  
     
     
         8 . A method according to  claim 4 , comprising the further steps of: 
 c. obtaining or synthesising said potential inhibitor;    d. forming a complex of PS and said potential inhibitor; and    e. analysing said complex by X-ray crystallography to determine the ability of said potential inhibitor to interact with PS.    
     
     
         9 . A compound identified as an inhibitor of PS by the method of  claim 4 .  
     
     
         10 . A method of forming a potential inhibitor of PS comprising the steps of: 
 a. employing a three-dimensional structure of PS, or at least one sub-domain thereof, to characterise a plurality of PS active sites, said three-dimensional structure being defined by atomic coordinate data according to Table 1;    b. designing or selecting respective compounds for interaction with said active sites; and    c. forming said potential inhibitor by linking said respective compounds into a larger compound which maintains the relative positions and orientations of said respective compounds at said active sites.    
     
     
         11 . A method according to  claim 10 , wherein step b. involves selecting said compounds by computationally screening a database of compounds for interaction with said active site.  
     
     
         12 . A method according to  claim 10 , comprising the further steps of: 
 d. obtaining or synthesising said potential inhibitor; and    e. contacting said potential inhibitor with PS to determine the ability of said potential inhibitor to interact with PS.    
     
     
         13 . A method according to  claim 12 , wherein in step d. said potential inhibitor is contacted with PS in the presence of a substrate to determine the ability of said potential inhibitor to inhibit PS.  
     
     
         14 . A method according to  claim 10 , comprising the further steps of: 
 d. obtaining or synthesising said potential inhibitor;    e. forming a complex of PS and said potential inhibitor; and    f. analysing said complex by X-ray crystallography to determine the ability of said potential inhibitor to interact with PS.    
     
     
         15 . A compound identified as an inhibitor of PS by the method of  claim 10 .  
     
     
         16 . A method of analysing a PS-ligand complex comprising the steps of: 
 a. employing (i) X-ray crystallographic diffraction data from said PS-ligand complex and (ii) a three-dimensional structure of PS, or at least one sub-domain thereof, to generate a difference Fourier electron density map of the complex, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and    b. analysing said difference Fourier electron density map.    
     
     
         17 . A computer readable medium with atomic data according to Table 1 recorded thereon, said data defining the three-dimensional structure of PS or at least one sub-domain thereof.  
     
     
         18 . A computer readable medium with structure factor data for PS recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1.  
     
     
         19 . A computer system containing atomic coordinate data according to Table 1, said data defining the three-dimensional structure of PS or at least one sub-domain thereof, and the system being intended to generate structures and/or perform rational drug design for PS or PS ligand complexes.  
     
     
         20 . A computer system containing structure factor data for PS, said structure factor data being derivable from the atomic coordinate data of Table 1, and the system being intended to generate structures and/or perform rational drug design for PS or PS ligand complexes.