The Mycobacterium Tuberculosis Structural Proteomics Project (XMTB)

 
aims to contribute to combat of one of most wide-spread and most lethal infectious diseases world-wide, tuberculosis.The initiative is funded by the German Ministry for Science and Education and it is coordinated by EMBL-Hamburg. It comprises four academic partners and three industrial partners in Germany.
   The overall goal of the XMTB-Structural Proteomics Consortium is to identify lead compounds against XMTB targets for drug discovery, using a structure based approach. The XMTB targets are selected by proteomics/transcriptomics oriented analyses of the MTB genome and those of related mycobacteria. The molecular structures of these targets are determined by X-ray crystallography. Small molecular ligands are identified and structurally mapped by a range of biophysical and NMR-based screening methods. Putative lead compounds are characterised and validated byin vivoscreening methods.
 
   The XMTB consortium cooperates with International partners, particularly with the American Mycobacterium Tuberculosis Structural Genomics Consortium.
     Up to December 2005 our consortium has deposited into RCSB Protein Data Bank the following structures:
 
Rv code Structure PDB code
Rv0491 + 1zkv
Rv0844 +  
Rv0858c +  
Rv0865 +  
Rv0902c + 1ys3; 1ysr
Rv0903c + 1ys6; 1ys7
Rv1293 +  
Rv1603 +  
Rv1612 +  
Rv1626 + 1s8n; 1sd5
Rv1689 +  
Rv2018 + 2bnt
Rv2140c + 2bt5
Rv2217 + 1w66
Rv2539c +  
Rv2540 +  
Rv2753c + 1xxx
Rv2773c + 1yl5; 1yl6; 1yl7
Rv2827c + 1zel
Rv2992 +  
Rv2995c + 1w0d
Rv3227 + 2bjb
Rv3280 + 2bzr
Rv3423c +  
Rv3472 +  

   The XMTB consortium performed number of automated screens for novel small molecule antagonist of Mycobacterium Tuberculosis. The following table summarize our results.

Rv code Target Function Hits/Library IC50 [uM] Specificity In vivo [uM]
Rv0764c CYP51 metabolic 23/20000 1-20 Profiling started 50
Rv2234 ptpA host signaling 17/20000 0.05-10 40 human N.D.
Rv0153c ptpB host signaling 18/20000 1-20 40 human N.D.
Rv2701c Inositol-1 monophosphatase signaling 212/23617 0.2-10 5 human N.D.
Rv2539c AroK metabolic 74/23617 1-20 N.D. N.D.
Rv3227 AroA metabolic 0/23617 - - -
Rv1402 PriA metabolic 87/20000 1.5-20 N.D. N.D.
Rv2995c IPMDH metabolic 125/20010 >25 N.D. N.D.
Rv2753c Dap A metabolic started - - -
Rv2773c Dap B metabolic started - - -
Rv0490 His-Kinase signaling started - - -
Rv2043c PNCA metabolic, MDR assay ready - - -
Rv3279c Biotin Ligase metabolic assay ready - - -
Rv2140c Raf-Kinase Inhib.Prot. host signaling assay set up - - -
Rv2217 lipB metabolic assay set up - - -
 

 

 

XMTB Scoreboard

STATUS

25.Sep.04

02.Mar.05

05.Sep.05

Selected ORF 182 197 197
Clones
(unique paire: vector, construct)
131 256 256
Expressed clones 126 192 192
Purified proteins 57 116 116
Purified soluble proteins 52 100 100
Crystals 24 44 51
Structures 9 23 40
Structures with ligand 1 10 10
Structures in PDB 3 8 10
HTP screening 0 54 54
NMR screening 0 10 10