4LV4

A noncompetitive inhibitor for M. tuberculosis's class IIa fructose 1,6-bisphosphate aldolase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.08 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A Noncompetitive Inhibitor for Mycobacterium tuberculosis's Class IIa Fructose 1,6-Bisphosphate Aldolase.

Capodagli, G.C.Sedhom, W.G.Jackson, M.Ahrendt, K.A.Pegan, S.D.

(2014) Biochemistry 53: 202-213

  • DOI: https://doi.org/10.1021/bi401022b
  • Primary Citation of Related Structures:  
    4LV4

  • PubMed Abstract: 

    Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, University of Denver , Denver, Colorado 80208, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fructose-bisphosphate aldolase349Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: fbaMT0379MTCY13E10.25cRv0363c
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
Binding Affinity Annotations 
IDSourceBinding Affinity
8HC Binding MOAD:  4LV4 Kd: 9390 (nM) from 1 assay(s)
BindingDB:  4LV4 Kd: 6940 (nM) from 1 assay(s)
IC50: min: 1.40e+4, max: 1.70e+4 (nM) from 2 assay(s)
ΔH: -2.87e+1 (kJ/mol) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.08 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.163 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.559α = 90
b = 118.933β = 90
c = 165.184γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-01-08
    Type: Initial release
  • Version 1.1: 2014-01-29
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description