Structures of human purine nucleoside phosphorylase complexed with inosine and ddI.
Human purine nucleoside phosphorylase (PNP) is a ubiquitous enzyme which plays a key role in the purine salvage pathway, and PNP deficiency in humans leads to an impairment of T-cell function, usually with no apparent effect on B-cell function. PNP is highly specific for 6-oxopurine nucleosides and exhibits negligible activity for 6-aminopurine nucleosides. The catalytic efficiency for inosine is 350,000-fold greater than for adenosine. Adenine nucleosides and nucleotides are deaminated by adenosine deaminase and AMP deaminase to their corresponding inosine derivatives which, in turn, may be further degraded. Here we report the crystal structures of human PNP in complex with inosine and 2('),3(')-dideoxyinosine, refined to 2.8A resolution using synchrotron radiation. The present structures provide explanation for ligand binding, refine the purine-binding site, and can be used for future inhibitor design.
Canduri
Fernanda
F
Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brazil.
dos Santos
Denis Marangoni
DM
Silva
Rafael Guimarães
RG
Mendes
Maria Anita
MA
Basso
Luiz Augusto
LA
Palma
Mário Sérgio
MS
de Azevedo
Walter Filgueira
WF
Santos
Diógenes Santiago
DS
D001665:Binding Sites; D018360:Crystallography, X-Ray; D016049:Didanosine / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007288:Inosine / Q000737:chemistry*; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
D008024:Ligands; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D016049:Didanosine