4UIO

Structure of the Salmonella typhi Type I Dehydroquinase covalently inhibited by a 3-dehydroquinic acid derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

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This is version 2.1 of the entry. See complete history


Literature

Chemical Modification of a Dehydratase Enzyme Involved in Bacterial Virulence by an Ammonium Derivative: Evidence of its Active Site Covalent Adduct.

Gonzalez-Bello, C.Tizon, L.Lence, E.Otero, J.M.van Raaij, M.J.Martinez-Guitian, M.Beceiro, A.Thompson, P.Hawkins, A.R.

(2015) J Am Chem Soc 137: 9333-9343

  • DOI: https://doi.org/10.1021/jacs.5b04080
  • Primary Citation of Related Structures:  
    4UIO

  • PubMed Abstract: 

    The first example of an ammonium derivative that causes a specific modification of the active site of type I dehydroquinase (DHQ1), a dehydratase enzyme that is a promising target for antivirulence drug discovery, is described. The resolution at 1.35 Å of the crystal structure of DHQ1 from Salmonella typhi chemically modified by this ammonium derivative revealed that the ligand is covalently attached to the essential Lys170 through the formation of an amine. The detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism and the experimentally observed differences between S. typhi and Staphylococcus aureus enzymes. The results presented here reveal that the replacement of Phe225 in St-DHQ1 by Tyr214 in Sa-DHQ1 and its hydrogen bonding interaction with the conserved water molecule observed in several crystal structures protects the amino adduct against further dehydration/aromatization reactions. In contrast, for the St-DHQ1 enzyme, the carboxylate group of Asp114, with the assistance of this water molecule, would trigger the formation of a Schiff base that can undergo further dehydration reactions until full aromatization of the cyclohexane ring is achieved. Moreover, in vitro antivirulence studies showed that the reported compound is able to reduce the ability of Salmonella Enteritidis to kill A459 respiratory cells. These studies have identified a good scaffold for the design of irreversible inhibitors that can be used as drugs and has opened up new opportunities for the development of novel antivirulence agents by targeting the DHQ1 enzyme.


  • Organizational Affiliation

    ∥Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CSIC), Campus Cantoblanco, 28049 Madrid, Spain.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-DEHYDROQUINATE DEHYDRATASE252Salmonella enterica subsp. enterica serovar TyphiMutation(s): 0 
EC: 4.2.1.10
UniProt
Find proteins for P24670 (Salmonella typhi)
Explore P24670 
Go to UniProtKB:  P24670
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24670
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: I 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.399α = 90
b = 42.327β = 105.13
c = 84.828γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALEdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-15
    Type: Initial release
  • Version 1.1: 2015-08-12
    Changes: Database references
  • Version 1.2: 2017-12-27
    Changes: Database references, Structure summary
  • Version 2.0: 2018-08-29
    Changes: Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description