3KGF

The structure of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis complexed with phenylalanine and tryptophan


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Synergistic allostery, a sophisticated regulatory network for the control of aromatic amino acid biosynthesis in Mycobacterium tuberculosis

Webby, C.J.Jiao, W.Hutton, R.D.Blackmore, N.J.Baker, H.M.Baker, E.N.Jameson, G.B.Parker, E.J.

(2010) J Biol Chem 285: 30567-30576

  • DOI: https://doi.org/10.1074/jbc.M110.111856
  • Primary Citation of Related Structures:  
    3KGF, 3NUD, 3NUE, 3NV8

  • PubMed Abstract: 

    The shikimate pathway, responsible for aromatic amino acid biosynthesis, is required for the growth of Mycobacterium tuberculosis and is a potential drug target. The first reaction is catalyzed by 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS). Feedback regulation of DAH7PS activity by aromatic amino acids controls shikimate pathway flux. Whereas Mycobacterium tuberculosis DAH7PS (MtuDAH7PS) is not inhibited by the addition of Phe, Tyr, or Trp alone, combinations cause significant loss of enzyme activity. In the presence of 200 μm Phe, only 2.4 μm Trp is required to reduce enzymic activity to 50%. Reaction kinetics were analyzed in the presence of inhibitory concentrations of Trp/Phe or Trp/Tyr. In the absence of inhibitors, the enzyme follows Michaelis-Menten kinetics with respect to substrate erythrose 4-phosphate (E4P), whereas the addition of inhibitor combinations caused significant homotropic cooperativity with respect to E4P, with Hill coefficients of 3.3 (Trp/Phe) and 2.8 (Trp/Tyr). Structures of MtuDAH7PS/Trp/Phe, MtuDAH7PS/Trp, and MtuDAH7PS/Phe complexes were determined. The MtuDAH7PS/Trp/Phe homotetramer binds four Trp and six Phe molecules. Binding sites for both aromatic amino acids are formed by accessory elements to the core DAH7PS (β/α)(8) barrel that are unique to the type II DAH7PS family and contribute to the tight dimer and tetramer interfaces. A comparison of the liganded and unliganded MtuDAH7PS structures reveals changes in the interface areas associated with inhibitor binding and a small displacement of the E4P binding loop. These studies uncover a previously unrecognized mode of control for the branched pathways of aromatic amino acid biosynthesis involving synergistic inhibition by specific pairs of pathway end products.


  • Organizational Affiliation

    From the Institute of Fundamental Sciences, Massey University, Palmerston North 4442, New Zealand.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Probable 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase AroG
A, B
464Mycobacterium tuberculosisMutation(s): 0 
Gene Names: Rv2178c
EC: 2.5.1.54
UniProt
Find proteins for O53512 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore O53512 
Go to UniProtKB:  O53512
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO53512
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TRP
Query on TRP

Download Ideal Coordinates CCD File 
D [auth A],
T [auth B]
TRYPTOPHAN
C11 H12 N2 O2
QIVBCDIJIAJPQS-VIFPVBQESA-N
PHE
Query on PHE

Download Ideal Coordinates CCD File 
AA [auth B],
C [auth A],
S [auth B]
PHENYLALANINE
C9 H11 N O2
COLNVLDHVKWLRT-QMMMGPOBSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
V [auth B],
W [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
PO4
Query on PO4

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A],
U [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
BA [auth B]
CA [auth B]
DA [auth B]
E [auth A]
EA [auth B]
BA [auth B],
CA [auth B],
DA [auth B],
E [auth A],
EA [auth B],
F [auth A],
FA [auth B],
K [auth A],
L [auth A],
M [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A],
Y [auth B],
Z [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
I [auth A],
X [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
J [auth A],
N [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 204.537α = 90
b = 204.537β = 90
c = 66.462γ = 120
Software Package:
Software NamePurpose
CrystalCleardata collection
CCP4model building
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling
CCP4phasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-02-22
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description