3S1G

tRNA-Guanine Transglycosylase in complex with lin-Benzohypoxanthine Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

From lin-Benzoguanines to lin-Benzohypoxanthines as Ligands for Zymomonas mobilis tRNA-Guanine Transglycosylase: Replacement of Protein-Ligand Hydrogen Bonding by Importing Water Clusters.

Barandun, L.J.Immekus, F.Kohler, P.C.Tonazzi, S.Wagner, B.Wendelspiess, S.Ritschel, T.Heine, A.Kansy, M.Klebe, G.Diederich, F.

(2012) Chemistry 18: 9246-9257

  • DOI: https://doi.org/10.1002/chem.201200809
  • Primary Citation of Related Structures:  
    3RR4, 3S1G, 3SM0, 3TLL

  • PubMed Abstract: 

    The foodborne illness shigellosis is caused by Shigella bacteria that secrete the highly cytotoxic Shiga toxin, which is also formed by the closely related enterohemorrhagic Escherichia coli (EHEC). It has been shown that tRNA-guanine transglycosylase (TGT) is essential for the pathogenicity of Shigella flexneri. Herein, the molecular recognition properties of a guanine binding pocket in Zymomonas mobilis TGT are investigated with a series of lin-benzohypoxanthine- and lin-benzoguanine-based inhibitors that bear substituents to occupy either the ribose-33 or the ribose-34 pocket. The three inhibitor scaffolds differ by the substituent at C(6) being H, NH(2), or NH-alkyl. These differences lead to major changes in the inhibition constants, pK(a) values, and binding modes. Compared to the lin-benzoguanines, with an exocyclic NH(2) at C(6), the lin-benzohypoxanthines without an exocyclic NH(2) group have a weaker affinity as several ionic protein-ligand hydrogen bonds are lost. X-ray cocrystal structure analysis reveals that a new water cluster is imported into the space vacated by the lacking NH(2) group and by a conformational shift of the side chain of catalytic Asp102. In the presence of an N-alkyl group at C(6) in lin-benzoguanine ligands, this water cluster is largely maintained but replacement of one of the water molecules in the cluster leads to a substantial loss in binding affinity. This study provides new insight into the role of water clusters at enzyme active sites and their challenging substitution by ligand parts, a topic of general interest in contemporary structure-based drug design.


  • Organizational Affiliation

    Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zurich, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Queuine tRNA-ribosyltransferase386Zymomonas mobilisMutation(s): 0 
Gene Names: tgtZMO0363
EC: 2.4.2.29
UniProt
Find proteins for P28720 (Zymomonas mobilis subsp. mobilis (strain ATCC 31821 / ZM4 / CP4))
Explore P28720 
Go to UniProtKB:  P28720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28720
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ITE Binding MOAD:  3S1G Ki: 6500 (nM) from 1 assay(s)
PDBBind:  3S1G Ki: 6500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.755α = 90
b = 64.753β = 95.87
c = 70.599γ = 90
Software Package:
Software NamePurpose
SHELXL-97refinement
CNSrefinement
MAR345dtbdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-16
    Type: Initial release
  • Version 1.1: 2012-07-18
    Changes: Database references
  • Version 1.2: 2012-08-29
    Changes: Database references
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description