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PDBsum entry 1q1g

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1q1g
Jmol
Contents
Protein chains
(+ 0 more) 243 a.a. *
Ligands
SO4 ×22
MTI ×6
IPA ×9
Waters ×357
* Residue conservation analysis
PDB id:
1q1g
Name: Transferase
Title: Crystal structure of plasmodium falciparum pnp with 5'-methy immucillin-h
Structure: Uridine phosphorylase putative. Chain: a, b, c, d, e, f. Engineered: yes
Source: Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Hexamer (from PQS)
Resolution:
2.02Å     R-factor:   0.211     R-free:   0.242
Authors: W.Shi,L.M.Ting,G.A.Kicska,A.Lewandowicz,P.C.Tyler,G.B.Evans, R.H.Furneaux,K.Kim,S.C.Almo,V.L.Schramm
Key ref:
W.Shi et al. (2004). Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem, 279, 18103-18106. PubMed id: 14982926 DOI: 10.1074/jbc.C400068200
Date:
19-Jul-03     Release date:   16-Mar-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q8I3X4  (Q8I3X4_PLAF7) -  Purine nucleotide phosphorylase, putative
Seq:
Struc:
245 a.a.
243 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.4.2.3  - Uridine phosphorylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Uridine + phosphate = uracil + alpha-D-ribose 1-phosphate
Uridine
Bound ligand (Het Group name = MTI)
matches with 42.31% similarity
+ phosphate
= uracil
+ alpha-D-ribose 1-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nucleoside metabolic process   1 term 
  Biochemical function     catalytic activity     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.C400068200 J Biol Chem 279:18103-18106 (2004)
PubMed id: 14982926  
 
 
Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function.
W.Shi, L.M.Ting, G.A.Kicska, A.Lewandowicz, P.C.Tyler, G.B.Evans, R.H.Furneaux, K.Kim, S.C.Almo, V.L.Schramm.
 
  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.
 
  Selected figure(s)  
 
Figure 2.
FIG. 2. X-ray crystal structure of PfPNP with ImmH and SO[4] at the catalytic sites. Panels show the hexamer (a) and stereo view of a single subunit (b). Panels were generated using SETOR (17).
Figure 3.
FIG. 3. Catalytic site contacts for ImmH and SO[4] at the catalytic sites of PfPNP (Protein Data Bank ID code 1NW4 [PDB] ) (a) compared with MT-ImmH and SO[4] in PfPNP (Protein Data Bank ID code 1Q1G [PDB] ) (b) and ImmH and PO[4] in bovine PNP (Protein Data Bank ID code 1B80 [PDB] ) (c). Amino acid residues labeled a in panels a and b are from the parent subunit, and those labeled b are from the neighbor subunit across the dimeric interface (see Fig. 2a). Distances are given in Angstroms. The lower panels are stereo views of electron density for the residues surrounding the catalytic sites of PfPNP (left) and human PNP (right). The stereo view of the channel in which the 5'-hydroxyl group of ImmH is bound is shown with the imino nitrogen of ImmH in blue and the 5'-hydroxyl oxygen in red (left). The oxygen points toward the viewer in a cavity of sufficient volume to accept a methylthio or homocysteine group. The cavity is filled with an isopropanol molecule from the solvent (shown in Fig. 4). Sulfate is bound in the cavity to the lower left and is yellow (S) and red (O). Human PNP·ImmH·PO[4] (right) has no open cavity (Protein Data Bank ID code 1RR6, unpublished observations). Electron density is a GRASP (18)-generated molecular surface for residues surrounding the catalytic site.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 18103-18106) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19669809 F.B.Zanchi, R.A.Caceres, R.G.Stabeli, and W.F.de Azevedo (2010).
Molecular dynamics studies of a hexameric purine nucleoside phosphorylase.
  J Mol Model, 16, 543-550.  
20057051 H.M.Pereira, M.M.Rezende, M.S.Castilho, G.Oliva, and R.C.Garratt (2010).
Adenosine binding to low-molecular-weight purine nucleoside phosphorylase: the structural basis for recognition based on its complex with the enzyme from Schistosoma mansoni.
  Acta Crystallogr D Biol Crystallogr, 66, 73-79.
PDB codes: 3e9r 3f8w 3faz 3fnq
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
19818813 P.M.Riegelhaupt, M.B.Cassera, R.F.Fröhlich, K.Z.Hazleton, J.J.Hefter, V.L.Schramm, and M.H.Akabas (2010).
Transport of purines and purine salvage pathway inhibitors by the Plasmodium falciparum equilibrative nucleoside transporter PfENT1.
  Mol Biochem Parasitol, 169, 40-49.  
19575810 A.Chaikuad, and R.L.Brady (2009).
Conservation of structure and activity in Plasmodium purine nucleoside phosphorylases.
  BMC Struct Biol, 9, 42.
PDB codes: 3emv 3enz
19778725 M.Ghanem, A.S.Murkin, and V.L.Schramm (2009).
Ribocation transition state capture and rebound in human purine nucleoside phosphorylase.
  Chem Biol, 16, 971-979.  
19191546 M.Ghanem, N.Zhadin, R.Callender, and V.L.Schramm (2009).
Loop-tryptophan human purine nucleoside phosphorylase reveals submillisecond protein dynamics.
  Biochemistry, 48, 3658-3668.  
18957439 D.C.Madrid, L.M.Ting, K.L.Waller, V.L.Schramm, and K.Kim (2008).
Plasmodium falciparum purine nucleoside phosphorylase is critical for viability of malaria parasites.
  J Biol Chem, 283, 35899-35907.  
18163886 K.Clark, M.Dhoogra, A.I.Louw, and L.M.Birkholtz (2008).
Transcriptional responses of Plasmodium falciparum to alpha-difluoromethylornithine-induced polyamine depletion.
  Biol Chem, 389, 111-125.  
18758447 L.M.Ting, M.Gissot, A.Coppi, P.Sinnis, and K.Kim (2008).
Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity.
  Nat Med, 14, 954-958.  
18799466 M.B.Cassera, K.Z.Hazleton, P.M.Riegelhaupt, E.F.Merino, M.Luo, M.H.Akabas, and V.L.Schramm (2008).
Erythrocytic adenosine monophosphate as an alternative purine source in Plasmodium falciparum.
  J Biol Chem, 283, 32889-32899.  
18567789 M.J.Downie, K.Kirk, and C.B.Mamoun (2008).
Purine salvage pathways in the intraerythrocytic malaria parasite Plasmodium falciparum.
  Eukaryot Cell, 7, 1231-1237.  
  20664707 S.Saen-Oon, V.L.Schramm, and S.D.Schwartz (2008).
Transition Path Sampling Study of the Reaction Catalyzed by Purine Nucleoside Phosphorylase.
  Z Phys Chem (N F), 222, 1359-1374.  
17266529 J.E.Hyde (2007).
Targeting purine and pyrimidine metabolism in human apicomplexan parasites.
  Curr Drug Targets, 8, 31-47.  
17875391 P.Gayathri, H.Balaram, and M.R.Murthy (2007).
Structural biology of plasmodial proteins.
  Curr Opin Struct Biol, 17, 744-754.  
16525558 K.Clinch, G.B.Evans, G.W.Fleet, R.H.Furneaux, S.W.Johnson, D.H.Lenz, S.P.Mee, P.R.Rands, V.L.Schramm, E.A.Taylor Ringia, and P.C.Tyler (2006).
Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases.
  Org Biomol Chem, 4, 1131-1139.  
16629674 M.J.Downie, K.J.Saliba, S.M.Howitt, S.Bröer, and K.Kirk (2006).
Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1.
  Mol Microbiol, 60, 738-748.  
16131758 C.Schnick, M.A.Robien, A.M.Brzozowski, E.J.Dodson, G.N.Murshudov, L.Anderson, J.R.Luft, C.Mehlin, W.G.Hol, J.A.Brannigan, and A.J.Wilkinson (2005).
Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine.
  Acta Crystallogr D Biol Crystallogr, 61, 1245-1254.
PDB codes: 1sq6 2bsx
  16511035 M.V.Dontsova, A.G.Gabdoulkhakov, O.K.Molchan, A.A.Lashkov, M.B.Garber, A.S.Mironov, N.E.Zhukhlistova, E.Y.Morgunova, W.Voelter, C.Betzel, Y.Zhang, S.E.Ealick, and A.M.Mikhailov (2005).
Preliminary investigation of the three-dimensional structure of Salmonella typhimurium uridine phosphorylase in the crystalline state.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 337-340.
PDB code: 1sj9
15983408 W.Bu, E.C.Settembre, M.H.el Kouni, and S.E.Ealick (2005).
Structural basis for inhibition of Escherichia coli uridine phosphorylase by 5-substituted acyclouridines.
  Acta Crystallogr D Biol Crystallogr, 61, 863-872.
PDB codes: 1u1c 1u1d 1u1e 1u1f 1u1g
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.