title: Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir.
abstract: 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.
authors.affiliation: Departamento de Física, UNESP, São José do Rio Preto, SP, Brazil.
authors.forename: Denis Marangoni
authors.initials: DM
authors.lastname: dos Santos
authors.forename: Fernanda
authors.initials: F
authors.lastname: Canduri
authors.forename: José Henrique
authors.initials: JH
authors.lastname: Pereira
authors.forename: Márcio
authors.initials: M
authors.lastname: Vinicius Bertacine Dias
authors.forename: Rafael Guimarães
authors.initials: RG
authors.lastname: Silva
authors.forename: Maria Anita
authors.initials: MA
authors.lastname: Mendes
authors.forename: Mário Sérgio
authors.initials: MS
authors.lastname: Palma
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.forename: Walter Filgueira
authors.initials: WF
authors.lastname: de Azevedo
authors.forename: Diógenes Santiago
authors.initials: DS
authors.lastname: Santos
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D046911:Macromolecular Substances; D010710:Phosphates; D011683:Purine-Nucleoside Phosphorylase; D000212:Acyclovir