4A22

Structure of Mycobacterium tuberculosis fructose 1,6-bisphosphate aldolase bound to N-(4-hydroxybutyl)- glycolohydroxamic acid bis- phosphate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Glycolytic and non-glycolytic functions of Mycobacterium tuberculosis fructose-1,6-bisphosphate aldolase, an essential enzyme produced by replicating and non-replicating bacilli.

de la Paz Santangelo, M.Gest, P.M.Guerin, M.E.Coincon, M.Pham, H.Ryan, G.Puckett, S.E.Spencer, J.S.Gonzalez-Juarrero, M.Daher, R.Lenaerts, A.J.Schnappinger, D.Therisod, M.Ehrt, S.Sygusch, J.Jackson, M.

(2011) J Biol Chem 286: 40219-40231

  • DOI: https://doi.org/10.1074/jbc.M111.259440
  • Primary Citation of Related Structures:  
    4A21, 4A22

  • PubMed Abstract: 

    The search for antituberculosis drugs active against persistent bacilli has led to our interest in metallodependent class II fructose-1,6-bisphosphate aldolase (FBA-tb), a key enzyme of gluconeogenesis absent from mammalian cells. Knock-out experiments at the fba-tb locus indicated that this gene is required for the growth of Mycobacterium tuberculosis on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme was exported to the cell surface of M. tuberculosis and produced under various axenic growth conditions including oxygen depletion and hence by non-replicating bacilli. Importantly, FBA-tb was also produced in vivo in the lungs of infected guinea pigs and mice. FBA-tb bound human plasmin(ogen) and protected FBA-tb-bound plasmin from regulation by α(2)-antiplasmin, suggestive of an involvement of this enzyme in host/pathogen interactions. The crystal structures of FBA-tb in the native form and in complex with a hydroxamate substrate analog were determined to 2.35- and 1.9-Å resolution, respectively. Whereas inhibitor attachment had no effect on the plasminogen binding activity of FBA-tb, it competed with the natural substrate of the enzyme, fructose 1,6-bisphosphate, and substantiated a previously unknown reaction mechanism associated with metallodependent aldolases involving recruitment of the catalytic zinc ion by the substrate upon active site binding. Altogether, our results highlight the potential of FBA-tb as a novel therapeutic target against both replicating and non-replicating bacilli.


  • Organizational Affiliation

    Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FRUCTOSE-BISPHOSPHATE ALDOLASE
A, B, C, D
344Mycobacterium tuberculosisMutation(s): 0 
EC: 4.1.2.13
UniProt
Find proteins for P9WQA3 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WQA3 
Go to UniProtKB:  P9WQA3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WQA3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TD4
Query on TD4

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
4-{hydroxy[(phosphonooxy)acetyl]amino}butyl dihydrogen phosphate
C6 H15 N O10 P2
GZQWGEFAYHQQKX-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
J [auth A]
K [auth A]
N [auth B]
O [auth B]
Q [auth C]
J [auth A],
K [auth A],
N [auth B],
O [auth B],
Q [auth C],
R [auth C],
T [auth D],
U [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

Download Ideal Coordinates CCD File 
I [auth A],
M [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
P [auth B]
S [auth C]
F [auth A],
G [auth A],
H [auth A],
P [auth B],
S [auth C],
V [auth D]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
TD4 Binding MOAD:  4A22 Kd: 6.8 (nM) from 1 assay(s)
BindingDB:  4A22 IC50: 3.2 (nM) from 1 assay(s)
PDBBind:  4A22 IC50: 3.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 335.386α = 90
b = 42.977β = 99.39
c = 102.601γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-12
    Type: Initial release
  • Version 1.1: 2011-10-26
    Changes: Atomic model
  • Version 1.2: 2011-11-16
    Changes: Atomic model
  • Version 1.3: 2011-11-30
    Changes: Database references
  • Version 2.0: 2018-11-21
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations