4B6P

Structure of Mycobacterium tuberculosis Type II Dehydroquinase inhibited by (2S)-2-Perfluorobenzyl-3-dehydroquinic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.172 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Mechanistic basis of the inhibition of type II dehydroquinase by (2S)- and (2R)-2-benzyl-3-dehydroquinic acids.

Lence, E.Tizon, L.Otero, J.M.Peon, A.Prazeres, V.F.Llamas-Saiz, A.L.Fox, G.C.van Raaij, M.J.Lamb, H.Hawkins, A.R.Gonzalez-Bello, C.

(2013) ACS Chem Biol 8: 568-577

  • DOI: https://doi.org/10.1021/cb300493s
  • Primary Citation of Related Structures:  
    4B6O, 4B6P, 4B6Q, 4B6R, 4B6S

  • PubMed Abstract: 

    The structural changes caused by the substitution of the aromatic moiety in (2S)-2-benzyl-3-dehydroquinic acids and its epimers in C2 by electron-withdrawing or electron-donating groups in type II dehydroquinase enzyme from M. tuberculosis and H. pylori has been investigated by structural and computational studies. Both compounds are reversible competitive inhibitors of this enzyme, which is essential in these pathogenic bacteria. The crystal structures of M. tuberculosis and H. pylori in complex with (2S)-2-(4-methoxy)benzyl- and (2S)-2-perfluorobenzyl-3-dehydroquinic acids have been solved at 2.0, 2.3, 2.0, and 1.9 Å, respectively. The crystal structure of M. tuberculosis in complex with (2R)-2-(benzothiophen-5-yl)methyl-3-dehydroquinic acid is also reported at 1.55 Å. These crystal structures reveal key differences in the conformation of the flexible loop of the two enzymes, a difference that depends on the presence of electron-withdrawing or electron-donating groups in the aromatic moiety of the inhibitors. This loop closes over the active site after substrate binding, and its flexibility is essential for the function of the enzyme. These differences have also been investigated by molecular dynamics simulations in an effort to understand the significant inhibition potency differences observed between some of these compounds and also to obtain more information about the possible movements of the loop. These computational studies have also allowed us to identify key structural factors of the H. pylori loop that could explain its reduced flexibility in comparison to the M. tuberculosis loop, specifically by the formation of a key salt bridge between the side chains of residues Asp18 and Arg20.


  • Organizational Affiliation

    Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Edificio CACTUS, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-DEHYDROQUINATE DEHYDRATASE146Mycobacterium tuberculosisMutation(s): 0 
EC: 4.2.1.10
UniProt
Find proteins for P9WPX7 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WPX7 
Go to UniProtKB:  P9WPX7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WPX7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2HN
Query on 2HN

Download Ideal Coordinates CCD File 
B [auth A](1R,2S,4S,5R)-2-(2,3,4,5,6-pentafluorophenyl)methyl-1,4,5-trihydroxy-3-oxocyclohexane-1-carboxylic acid
C14 H11 F5 O6
ZNZHQTVBMHBUCF-GLOYCNQYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
2HN PDBBind:  4B6P Ki: 74 (nM) from 1 assay(s)
Binding MOAD:  4B6P Ki: 74 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.172 
  • Space Group: F 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 126.27α = 90
b = 126.27β = 90
c = 126.27γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata 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: 2012-12-19
    Type: Initial release
  • Version 1.1: 2013-03-20
    Changes: Other
  • Version 1.2: 2013-03-27
    Changes: Database references
  • Version 1.3: 2013-08-07
    Changes: Non-polymer description
  • Version 1.4: 2018-01-17
    Changes: Database references
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description