RCSB PDB - 7PBA: Crystal structure of CD73 in complex with IMP in the open form

 7PBA

Crystal structure of CD73 in complex with IMP in the open form


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.168 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.130 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5'-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives.

Scaletti, E.Huschmann, F.U.Mueller, U.Weiss, M.S.Strater, N.

(2021) Purinergic Signal 17: 693-704

  • DOI: https://doi.org/10.1007/s11302-021-09802-w
  • Primary Citation of Related Structures:  
    7P9N, 7P9R, 7P9T, 7PA4, 7PB5, 7PBA, 7PBB, 7PBY, 7PCP, 7PD9

  • PubMed Abstract: 

    Human ecto-5-nucleotidase (CD73) is involved in purinergic signalling, which influences a diverse range of biological processes. CD73 hydrolyses AMP and is the major control point for the levels of extracellular adenosine. Inhibitors of CD73 thus block the immunosuppressive action of adenosine, a promising approach for cancer immunotherapy. Interestingly, ADP and ATP are competitive inhibitors of CD73, with the most potent small-molecule inhibitors to date being non-hydrolysable ADP analogues. While AMP is the major substrate of the enzyme, CD73 has been reported to hydrolyse other 5'-nucleoside monophosphates. Based on a fragment screening campaign at the BESSY II synchrotron, we present the binding modes of various deoxyribo- and ribonucleoside monophosphates and of four additional fragments binding to the nucleoside binding site of the open form of the enzyme. Kinetic analysis of monophosphate hydrolysis shows that ribonucleotide substrates are favoured over their deoxyribose equivalents with AMP being the best substrate. We characterised the initial step of AMP hydrolysis, the binding mode of AMP to the open conformation of CD73 and compared that to other monophosphate substrates. In addition, the inhibitory activity of various bisphosphonic acid derivatives of nucleoside diphosphates was determined. Although AMPCP remains the most potent inhibitor, replacement of the adenine base with other purines or with pyrimidines increases the K i value only between twofold and sixfold. On the other hand, these nucleobases offer new opportunities to attach substituents for improved pharmacological properties.


  • Organizational Affiliation

    Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
5'-nucleotidase546Homo sapiensMutation(s): 8 
Gene Names: NT5ENT5NTE
EC: 3.1.3.5 (PDB Primary Data), 3.1.3.99 (UniProt), 3.1.3.89 (UniProt), 3.1.3.35 (UniProt), 3.1.3.91 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P21589 (Homo sapiens)
Explore P21589 
Go to UniProtKB:  P21589
PHAROS:  P21589
GTEx:  ENSG00000135318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21589
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.42 Å
  • R-Value Free: 0.168 
  • R-Value Work: 0.128 
  • R-Value Observed: 0.130 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.711α = 90
b = 131.852β = 90
c = 66.634γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted IMPClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2021-10-13
    Type: Initial release
  • Version 1.1: 2021-12-29
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Refinement description
  • Version 1.3: 2024-11-13
    Changes: Structure summary