PDBsum entry 3c2y

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protein ligands metals links
Transferase PDB id
Protein chain
361 a.a. *
GOL ×5
Waters ×274
* Residue conservation analysis
PDB id:
Name: Transferase
Title: tRNA-guanine transglycosylase (tgt) in complex with 6-amino- 1,7-dihydro-imidazo[4,5-g]quinazolin-8-one
Structure: Queuine tRNA-ribosyltransferase. Chain: a. Synonym: tRNA-guanine transglycosylase, guanine insertion e tgt. Engineered: yes
Source: Zymomonas mobilis. Organism_taxid: 542. Gene: tgt. Expressed in: escherichia coli. Expression_system_taxid: 562.
1.78Å     R-factor:   0.164     R-free:   0.214
Authors: T.Ritschel,A.Heine,G.Klebe
Key ref: T.Ritschel et al. (2009). Crystal structure analysis and in silico pKa calculations suggest strong pKa shifts of ligands as driving force for high-affinity binding to TGT. Chembiochem, 10, 716-727. PubMed id: 19199329
26-Jan-08     Release date:   03-Feb-09    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P28720  (TGT_ZYMMO) -  Queuine tRNA-ribosyltransferase
386 a.a.
361 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - tRNA-guanine(34) transglycosylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
1. Guanine34 in tRNA + queuine = queuosine34 in tRNA + guanine
2. Guanine34 in tRNA + 7-aminomethyl-7-carbaguanine = 7-aminomethyl-7- carbaguanine34 in tRNA + guanine
Guanine(34) in tRNA
Bound ligand (Het Group name = S60)
matches with 61.11% similarity
= queuosine(34) in tRNA
+ guanine
Guanine(34) in tRNA
Bound ligand (Het Group name = S60)
matches with 70.59% similarity
= 7-aminomethyl-7- carbaguanine(34) in tRNA
+ guanine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     tRNA processing   3 terms 
  Biochemical function     transferase activity     4 terms  


Chembiochem 10:716-727 (2009)
PubMed id: 19199329  
Crystal structure analysis and in silico pKa calculations suggest strong pKa shifts of ligands as driving force for high-affinity binding to TGT.
T.Ritschel, S.Hoertner, A.Heine, F.Diederich, G.Klebe.
A novel ligand series is presented to inhibit tRNA-guanine transglycosylase (TGT), a protein with a significant role in the pathogenicity mechanism of Shigella flexneri, the causative agent of Shigellosis. The enzyme exchanges guanine in the wobble position of tRNA(Asn,Asp,His,Tyr) against a modified base. To prevent the base-exchange reaction, several series of inhibitors have already been designed, synthesized, and tested. One aim of previous studies was to address a hydrophobic pocket with different side chains attached to the parent skeletons. Disappointingly, no significant increase in binding affinity could be observed that could be explained by the disruption of a conserved water cluster. The ligand series examined in this study are based on the known scaffold lin-benzoguanine. Different side chains were introduced leading to 2-amino-lin-benzoguanines, which address a different pocket of the protein and avoid disruption of the water cluster. With the introduction of an amino group in the 2-position, a dramatic increase in binding affinity can be experienced. To explain this significant gain in binding affinity, Poisson-Boltzmann calculations were performed to explore pK(a) changes of ligand functional groups upon protein binding, they can differ significantly on going from aqueous solution to protein environment. For all complexes, a permanent protonation of the newly designed ligands is suggested, leading to a charge-assisted hydrogen bond in the protein-ligand complex. This increased strength in hydrogen bonding takes beneficial effect on binding affinity of the ligands, resulting in low-nanomolar binders. Crystal structures and docking emphasize the importance of the newly created charge-assisted hydrogen bond. A detailed analysis of the crystal structures in complex with substituted 2-amino-lin-benzoguanines indicate pronounced disorder of the attached side chains addressing the ribose 33 binding pocket. Docking suggests multiple orientations of these side chains. Obviously, an entropic advantage of the residual mobility experienced by these ligands in the bound state is beneficial and reveals an overall improved protein binding.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19746363 P.C.Kohler, T.Ritschel, W.B.Schweizer, G.Klebe, and F.Diederich (2009).
High-affinity inhibitors of tRNA-guanine transglycosylase replacing the function of a structural water cluster.
  Chemistry, 15, 10809-10817.  
19894214 T.Ritschel, P.C.Kohler, G.Neudert, A.Heine, F.Diederich, and G.Klebe (2009).
How to Replace the Residual Solvation Shell of Polar Active Site Residues to Achieve Nanomolar Inhibition of tRNA-Guanine Transglycosylase.
  ChemMedChem, 4, 2012-2023.
PDB codes: 3eos 3eou 3gc4 3gc5 3ge7
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