7ZSO

human purine nucleoside phosphorylase in complex with JS-554


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors.

Skacel, J.Djukic, S.Baszczynski, O.Kalcic, F.Bilek, T.Chalupsky, K.Kozak, J.Dvorakova, A.Tloust'ova, E.Kral'ova, Z.Smidkova, M.Voldrich, J.Rumlova, M.Pachl, P.Brynda, J.Vuckova, T.Fabry, M.Snasel, J.Pichova, I.Rezacova, P.Mertlikova-Kaiserova, H.Janeba, Z.

(2023) J Med Chem 66: 6652-6681

  • DOI: https://doi.org/10.1021/acs.jmedchem.2c02097
  • Primary Citation of Related Structures:  
    7ZSL, 7ZSM, 7ZSN, 7ZSO, 7ZSP, 7ZSQ, 7ZSR, 8C25

  • PubMed Abstract: 

    Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC 50 values as low as 19 nM (human PNP) and 4 nM ( Mycobacterium tuberculosis ( Mt ) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC 50 values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 μM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme ( Mt PNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo .


  • Organizational Affiliation

    Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Flemingovo nám. 2, Prague 16610, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Purine nucleoside phosphorylase
A, B, C
289Homo sapiensMutation(s): 0 
Gene Names: PNPNP
EC: 2.4.2.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00491 (Homo sapiens)
Explore P00491 
Go to UniProtKB:  P00491
PHAROS:  P00491
GTEx:  ENSG00000198805 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00491
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JTC (Subject of Investigation/LOI)
Query on JTC

Download Ideal Coordinates CCD File 
D [auth A],
O [auth B],
S [auth C]
[(~{E})-2-[2-[(4-oxidanylidene-3,5-dihydropyrrolo[3,2-d]pyrimidin-7-yl)sulfanyl]-5-[2,3,4,5,6-pentakis(fluoranyl)phenoxy]phenyl]ethenyl]phosphonic acid
C20 H11 F5 N3 O5 P S
IMXBQYQAJSJWFZ-ONEGZZNKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth C]
BA [auth C]
G [auth A]
H [auth A]
I [auth A]
AA [auth C],
BA [auth C],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
P [auth B],
Q [auth B],
R [auth B],
U [auth C],
V [auth C],
W [auth C],
X [auth C],
Y [auth C],
Z [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
T [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
CA [auth C],
N [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.48α = 90
b = 119.33β = 90
c = 130.18γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Regional Development FundEuropean UnionCZ.02.1.01/0.0/0.0/16_019/0000729

Revision History  (Full details and data files)

  • Version 1.0: 2023-05-17
    Type: Initial release
  • Version 1.1: 2023-05-24
    Changes: Database references
  • Version 1.2: 2023-06-07
    Changes: Database references
  • Version 1.3: 2024-02-07
    Changes: Data collection