3N7A

Crystal structure of 3-dehydroquinate dehydratase from Mycobacterium tuberculosis in complex with inhibitor 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.181 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis.

Dias, M.V.Snee, W.C.Bromfield, K.M.Payne, R.J.Palaninathan, S.K.Ciulli, A.Howard, N.I.Abell, C.Sacchettini, J.C.Blundell, T.L.

(2011) Biochem J 436: 729-739

  • DOI: https://doi.org/10.1042/BJ20110002
  • Primary Citation of Related Structures:  
    3N59, 3N76, 3N7A, 3N86, 3N87, 3N8K, 3N8N

  • PubMed Abstract: 

    The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19-24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.


  • Organizational Affiliation

    Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-dehydroquinate dehydratase
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X
147Mycobacterium tuberculosisMutation(s): 0 
Gene Names: aroDaroQMT2612MTCY159.19Rv2537c
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
FA1
Query on FA1

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth C]
BB [auth T]
CA [auth D]
DB [auth U]
AA [auth B],
BA [auth C],
BB [auth T],
CA [auth D],
DB [auth U],
EA [auth E],
FA [auth F],
FB [auth V],
GB [auth W],
HA [auth G],
IB [auth X],
JA [auth H],
LA [auth I],
MA [auth J],
NA [auth K],
PA [auth L],
QA [auth M],
RA [auth N],
TA [auth O],
VA [auth P],
XA [auth Q],
Y [auth A],
YA [auth R],
ZA [auth S]
2,3 -ANHYDRO-QUINIC ACID
C7 H10 O5
VTEDVYGIJPLVFF-XAHCXIQSSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AB [auth T]
CB [auth U]
DA [auth E]
EB [auth V]
GA [auth G]
AB [auth T],
CB [auth U],
DA [auth E],
EB [auth V],
GA [auth G],
HB [auth X],
IA [auth H],
KA [auth I],
OA [auth L],
SA [auth O],
UA [auth P],
WA [auth Q],
Z [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FA1 BindingDB:  3N7A Ki: 2.00e+5 (nM) from 1 assay(s)
Kd: 2.00e+5 (nM) from 1 assay(s)
PDBBind:  3N7A Ki: 2.00e+5 (nM) from 1 assay(s)
Binding MOAD:  3N7A Ki: 2.00e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.181 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.912α = 79.93
b = 95.557β = 80.3
c = 124.47γ = 77.6
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-05-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description