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PDBsum entry 2isc

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2isc
Jmol
Contents
Protein chains
(+ 0 more) 227 a.a. *
Ligands
PO4 ×8
223 ×6
Waters ×160
* Residue conservation analysis
PDB id:
2isc
Name: Transferase
Title: Crystal stucture of purine nucleoside phosphorylase from trichomonas vaginalis with dadme-imm-a
Structure: Purine nucleoside phosphorylase. Chain: a, b, c, d, e, f. Synonym: pnp. Engineered: yes
Source: Trichomonas vaginalis. Organism_taxid: 5722. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.70Å     R-factor:   0.202     R-free:   0.252
Authors: A.Rinaldo-Matthis,S.C.Almo,V.L.Schramm
Key ref: A.Rinaldo-Matthis et al. (2007). Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues. Biochemistry, 46, 659-668. PubMed id: 17223688
Date:
17-Oct-06     Release date:   05-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
A2E7Y6  (A2E7Y6_TRIVA) -  Purine nucleoside phosphorylase, putative
Seq:
Struc:
236 a.a.
227 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nucleobase-containing compound metabolic process   2 terms 
  Biochemical function     catalytic activity     2 terms  

 

 
Biochemistry 46:659-668 (2007)
PubMed id: 17223688  
 
 
Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues.
A.Rinaldo-Matthis, C.Wing, M.Ghanem, H.Deng, P.Wu, A.Gupta, P.C.Tyler, G.B.Evans, R.H.Furneaux, S.C.Almo, C.C.Wang, V.L.Schramm.
 
  ABSTRACT  
 
Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP x ImmA x PO4 and TvPNP x DADMe-ImmA x PO4 ternary complexes differ from previous structures with substrate analogues. The tight binding with DADMe-ImmA is in part due to a 2.7 A ionic interaction between a PO4 oxygen and the N1' cation of the hydroxypyrrolidine and is weaker in the TvPNP x ImmA x PO4 structure at 3.5 A. However, the TvPNP x ImmA x PO4 structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP x DADMe-ImmA x PO4. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-18O]ImmH to establish that O6 is the keto tautomer in TvPNP x ImmH x PO4, causing an unfavorable leaving-group interaction.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21169694 H.D'Muniz Pereira, G.Oliva, and R.C.Garratt (2011).
Purine nucleoside phosphorylase from Schistosoma mansoni in complex with ribose-1-phosphate.
  J Synchrotron Radiat, 18, 62-65.
PDB code: 3fb1
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
19170524 K.Clinch, G.B.Evans, R.F.Fröhlich, R.H.Furneaux, P.M.Kelly, L.Legentil, A.S.Murkin, L.Li, V.L.Schramm, P.C.Tyler, and A.D.Woolhouse (2009).
Third-generation immucillins: syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase.
  J Med Chem, 52, 1126-1143.  
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.  
17548352 I.Basu, G.Cordovano, I.Das, T.J.Belbin, C.Guha, and V.L.Schramm (2007).
A transition state analogue of 5'-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers.
  J Biol Chem, 282, 21477-21486.  
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 code is shown on the right.