4CD1

RnNTPDase2 in complex with PSB-071


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

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This is version 1.1 of the entry. See complete history


Literature

Crystal Structure of Ntpdase2 in Complex with the Sulfoanthraquinone Inhibitor Psb-071.

Zebisch, M.Baqi, Y.Schafer, P.Muller, C.E.Strater, N.

(2014) J Struct Biol 185: 336

  • DOI: https://doi.org/10.1016/j.jsb.2014.01.005
  • Primary Citation of Related Structures:  
    4CD1, 4CD3

  • PubMed Abstract: 

    In many vertebrate tissues CD39-like ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) act in concert with ecto-5'-nucleotidase (e5NT, CD73) to convert extracellular ATP to adenosine. Extracellular ATP is a cytotoxic, pro-inflammatory signalling molecule whereas its product adenosine constitutes a universal and potent immune suppressor. Interference with these ectonucleotidases by use of small molecule inhibitors or inhibitory antibodies appears to be an effective strategy to enhance anti-tumour immunity and suppress neoangiogenesis. Here we present the first crystal structures of an NTPDase catalytic ectodomain in complex with the Reactive Blue 2 (RB2)-derived inhibitor PSB-071. In both of the two crystal forms presented the inhibitor binds as a sandwich of two molecules at the nucleoside binding site. One of the molecules is well defined in its orientation. Specific hydrogen bonds are formed between the sulfonyl group and the nucleoside binding loop. The methylphenyl side chain functionality that improved NTPDase2-specificity is sandwiched between R245 and R394, the latter of which is exclusively found in NTPDase2. The second molecule exhibits great in-plane rotational freedom and could not be modelled in a specific orientation. In addition to this structural insight into NTPDase inhibition, the observation of the putative membrane interaction loop (MIL) in two different conformations related by a 10° rotation identifies the MIL as a dynamic section of NTPDases that is potentially involved in regulation of catalysis.


  • Organizational Affiliation

    Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany; Division of Structural Biology, University of Oxford, Roosevelt Drive, Oxford OX3-7BN, United Kingdom. Electronic address: matthias@strubi.ox.ac.uk.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ECTONUCLEOSIDE TRIPHOSPHATE DIPHOSPHOHYDROLASE 2457Rattus norvegicusMutation(s): 0 
EC: 3.6.1 (PDB Primary Data), 3.6.1.5 (PDB Primary Data)
UniProt
Find proteins for O35795 (Rattus norvegicus)
Explore O35795 
Go to UniProtKB:  O35795
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO35795
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8E9
Query on 8E9

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
1-AMINO-4-(3-METHYLPHENYL)AMINO-9,10-DIOXO-9,10-DIHYDROANTHRACENE-2-SULFONATE
C21 H16 N2 O5 S
AYMOWRNYHLSUHI-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.007α = 90
b = 68.04β = 90
c = 162.389γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-12
    Type: Initial release
  • Version 1.1: 2014-03-12
    Changes: Database references