4DDK

Pantothenate synthetase in complex with 1,3-benzodioxole-5-carboxylic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.

Silvestre, H.L.Blundell, T.L.Abell, C.Ciulli, A.

(2013) Proc Natl Acad Sci U S A 110: 12984-12989

  • DOI: https://doi.org/10.1073/pnas.1304045110
  • Primary Citation of Related Structures:  
    4DDH, 4DDK, 4DDM, 4DE5, 4EF6, 4EFK, 4FZJ, 4G5F, 4G5Y

  • PubMed Abstract: 

    In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors.


  • Organizational Affiliation

    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pantothenate synthetase
A, B
301Mycobacterium tuberculosisMutation(s): 2 
Gene Names: MT3707MTCY07H7B.20panCRv3602c
EC: 6.3.2.1
UniProt
Find proteins for P9WIL5 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WIL5 
Go to UniProtKB:  P9WIL5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WIL5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0HN
Query on 0HN

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B],
H [auth B]
1,3-benzodioxole-5-carboxylic acid
C8 H6 O4
VDVJGIYXDVPQLP-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
I [auth B],
J [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
L [auth B]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
EOH
Query on EOH

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B]
ETHANOL
C2 H6 O
LFQSCWFLJHTTHZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0HN PDBBind:  4DDK Kd: 5.10e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.19α = 90
b = 70.71β = 99.14
c = 81.69γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
AMoREphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-02-13
    Type: Initial release
  • Version 1.1: 2013-08-07
    Changes: Database references
  • Version 1.2: 2013-09-04
    Changes: Database references
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description