Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir

• Published in: Biochemical and biophysical research communications 2003-08, Vol.308 (3), p.553-559
• Main Authors: dos Santos, Denis Marangoni, Canduri, Fernanda, Pereira, José Henrique, Vinicius Bertacine Dias, Márcio, Silva, Rafael Guimarães, Mendes, Maria Anita, Palma, Mário Sérgio, Basso, Luiz Augusto, de Azevedo, Walter Filgueira, Santos, Diógenes Santiago
• Format: Article
• Language: English
• Subjects: Acyclovir; Acyclovir - chemistry; Acyclovir - metabolism; Binding Sites; Crystallography, X-Ray; Drug design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Hydrogen Bonding; Ligands; Macromolecular Substances; Models, Molecular; Phosphates - chemistry; PNP; Protein Conformation; Purine-Nucleoside Phosphorylase - chemistry; Purine-Nucleoside Phosphorylase - metabolism; Structure; Synchrotron radiation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)01433-5

In human, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design. This work reports the first crystallographic study of human PNP complexed with acyclovir (HsPNP:Acy). Acyclovir is a potent clinically useful inhibitor of replicant herpes simplex virus that also inhibits human PNP but with a relatively lower inhibitory activity ( K i =90 μM ). Analysis of the structural differences among the HsPNP:Acy complex, PNP apoenzyme, and HsPNP:Immucillin-H provides explanation for inhibitor binding, refines the purine-binding site, and can be used for future inhibitor design.