5KGS

Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with an inhibitor optimized from HTS lead: 5-[4-(1,3-benzodioxol-5-ylcarbonyl)piperazin-1-yl]-2,3-dihydroinden-1-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.

Liu, F.Dawadi, S.Maize, K.M.Dai, R.Park, S.W.Schnappinger, D.Finzel, B.C.Aldrich, C.C.

(2017) J Med Chem 60: 5507-5520

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00189
  • Primary Citation of Related Structures:  
    4XJO, 4XJP, 5KGS, 5KGT

  • PubMed Abstract: 

    The pyridoxal 5'-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a K D of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Adenosylmethionine-8-amino-7-oxononanoate aminotransferase
A, B
457Mycobacterium tuberculosis variant bovis AF2122/97Mutation(s): 0 
Gene Names: bioAMb1595
EC: 2.6.1.62
UniProt
Find proteins for P0A4X7 (Mycobacterium bovis (strain ATCC BAA-935 / AF2122/97))
Explore P0A4X7 
Go to UniProtKB:  P0A4X7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A4X7
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.186α = 90
b = 65.948β = 90
c = 203.898γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR01AI091790

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-14
    Type: Initial release
  • Version 1.1: 2017-06-21
    Changes: Database references
  • Version 1.2: 2017-07-05
    Changes: Database references
  • Version 1.3: 2017-07-26
    Changes: Database references
  • Version 1.4: 2017-09-20
    Changes: Author supporting evidence
  • Version 1.5: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.6: 2023-09-27
    Changes: Data collection, Database references, Refinement description