Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir.
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 microM). 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.
dos Santos
Denis Marangoni
DM
Departamento de Física, UNESP, São José do Rio Preto, SP, Brazil.
Canduri
Fernanda
F
Pereira
José Henrique
JH
Vinicius Bertacine Dias
Márcio
M
Silva
Rafael Guimarães
RG
Mendes
Maria Anita
MA
Palma
Mário Sérgio
MS
Basso
Luiz Augusto
LA
de Azevedo
Walter Filgueira
WF
Santos
Diógenes Santiago
DS
D000212:Acyclovir / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D046911:Macromolecular Substances; D010710:Phosphates; D011683:Purine-Nucleoside Phosphorylase; D000212:Acyclovir