4BFX

Crystal structure of Mycobacterium tuberculosis PanK in complex with a triazole inhibitory compound (1f) and phosphate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.209 

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This is version 1.4 of the entry. See complete history


Literature

Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium Tuberculosis Pank

Bjorkelid, C.Bergfors, T.Raichurkar, A.K.V.Mukherjee, K.Krishnan, M.Bandodkar, B.Jones, T.A.

(2013) J Biol Chem 288: 18260

  • DOI: https://doi.org/10.1074/jbc.M113.476473
  • Primary Citation of Related Structures:  
    4BFS, 4BFT, 4BFU, 4BFV, 4BFW, 4BFX, 4BFY, 4BFZ

  • PubMed Abstract: 

    Mycobacterium tuberculosis, the bacterial causative agent of tuberculosis, currently affects millions of people. The emergence of drug-resistant strains makes development of new antibiotics targeting the bacterium a global health priority. Pantothenate kinase, a key enzyme in the universal biosynthesis of the essential cofactor CoA, was targeted in this study to find new tuberculosis drugs. The biochemical characterizations of two new classes of compounds that inhibit pantothenate kinase from M. tuberculosis are described, along with crystal structures of their enzyme-inhibitor complexes. These represent the first crystal structures of this enzyme with engineered inhibitors. Both classes of compounds bind in the active site of the enzyme, overlapping with the binding sites of the natural substrate and product, pantothenate and phosphopantothenate, respectively. One class of compounds also interferes with binding of the cofactor ATP. The complexes were crystallized in two crystal forms, one of which is in a new space group for this enzyme and diffracts to the highest resolution reported for any pantothenate kinase structure. These two crystal forms allowed, for the first time, modeling of the cofactor-binding loop in both open and closed conformations. The structures also show a binding mode of ATP different from that previously reported for the M. tuberculosis enzyme but similar to that in the pantothenate kinases of other organisms.


  • Organizational Affiliation

    Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, SE-751 24 Uppsala, Sweden. christofer@xray.bmc.uu.se


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PANTOTHENATE KINASE
A, B
318Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 2.7.1.33
UniProt
Find proteins for P9WPA7 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WPA7 
Go to UniProtKB:  P9WPA7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WPA7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
ZVX BindingDB:  4BFX IC50: min: 1090, max: 1.40e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.01α = 90
b = 149.51β = 90
c = 62.83γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-15
    Type: Initial release
  • Version 1.1: 2013-05-22
    Changes: Database references
  • Version 1.2: 2013-07-10
    Changes: Database references
  • Version 1.3: 2019-03-06
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2019-05-15
    Changes: Data collection, Experimental preparation