1NW4

Crystal Structure of Plasmodium falciparum Purine Nucleoside Phosphorylase in complex with ImmH and Sulfate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Plasmodium falciparum Purine Nucleoside Phosphorylase: CRYSTAL STRUCTURES, IMMUCILLIN INHIBITORS, AND DUAL CATALYTIC FUNCTION.

Shi, W.Ting, L.M.Kicska, G.A.Lewandowicz, A.Tyler, P.C.Evans, G.B.Furneaux, R.H.Kim, K.Almo, S.C.Schramm, V.L.

(2004) J Biol Chem 279: 18103-18106

  • DOI: https://doi.org/10.1074/jbc.C400068200
  • Primary Citation of Related Structures:  
    1NW4, 1Q1G, 1RR6

  • PubMed Abstract: 

    Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action.


  • Organizational Affiliation

    Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
uridine phosphorylase, putative
A, B, C, D, E
A, B, C, D, E, F
276Plasmodium falciparum 3D7Mutation(s): 0 
EC: 2.4.2.1
UniProt
Find proteins for Q8I3X4 (Plasmodium falciparum (isolate 3D7))
Explore Q8I3X4 
Go to UniProtKB:  Q8I3X4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8I3X4
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IMH
Query on IMH

Download Ideal Coordinates CCD File 
DA [auth D]
JA [auth E]
K [auth A]
QA [auth F]
R [auth B]
DA [auth D],
JA [auth E],
K [auth A],
QA [auth F],
R [auth B],
Y [auth C]
1,4-DIDEOXY-4-AZA-1-(S)-(9-DEAZAHYPOXANTHIN-9-YL)-D-RIBITOL
C11 H14 N4 O4
IWKXDMQDITUYRK-KUBHLMPHSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth D]
BA [auth D]
CA [auth D]
G [auth A]
GA [auth E]
AA [auth D],
BA [auth D],
CA [auth D],
G [auth A],
GA [auth E],
H [auth A],
HA [auth E],
I [auth A],
IA [auth E],
J [auth A],
MA [auth F],
NA [auth F],
O [auth B],
OA [auth F],
P [auth B],
PA [auth F],
Q [auth B],
W [auth C],
X [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
IPA
Query on IPA

Download Ideal Coordinates CCD File 
EA [auth D]
FA [auth D]
KA [auth E]
L [auth A]
LA [auth E]
EA [auth D],
FA [auth D],
KA [auth E],
L [auth A],
LA [auth E],
M [auth A],
N [auth A],
RA [auth F],
S [auth B],
SA [auth F],
T [auth B],
TA [auth F],
U [auth B],
V [auth B],
Z [auth C]
ISOPROPYL ALCOHOL
C3 H8 O
KFZMGEQAYNKOFK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
IMH PDBBind:  1NW4 Kd: 0.86 (nM) from 1 assay(s)
Binding MOAD:  1NW4 Kd: 0.86 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.554α = 90
b = 92.285β = 90
c = 239.64γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-16
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Source and taxonomy, Version format compliance
  • Version 2.0: 2022-10-05
    Changes: Atomic model, Database references, Derived calculations, Experimental preparation, Structure summary
  • Version 2.1: 2023-09-20
    Changes: Data collection, Refinement description