Crystal structure of human PNP complexed with guanine.
Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides. PNP is a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design. More recently, the 3-D structure of human PNP has been refined to 2.3A resolution, which allowed a redefinition of the residues involved in the substrate-binding sites and provided a more reliable model for structure-based design of inhibitors. This work reports crystallographic study of the complex of Human PNP:guanine (HsPNP:Gua) solved at 2.7A resolution using synchrotron radiation. Analysis of the structural differences among the HsPNP:Gua 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.
de Azevedo
Walter Filgueira
WF
Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brazil. walterfa@df.ibilce.unesp.br
Canduri
Fernanda
F
dos Santos
Denis Marangoni
DM
Pereira
José Henrique
JH
Bertacine Dias
Márcio Vinicius
MV
Silva
Rafael Guimarães
RG
Mendes
Maria Anita
MA
Basso
Luiz Augusto
LA
Palma
Mário Sérgio
MS
Santos
Diógenes Santiago
DS
D001665:Binding Sites; D003198:Computer Simulation; D003460:Crystallization / Q000379:methods*; D003461:Crystallography / Q000379:methods*; D004789:Enzyme Activation; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry*; D012996:Solutions; D013379:Substrate Specificity; D013722:Teprotide; D014867:Water / Q000737:chemistry*
D046911:Macromolecular Substances; D010710:Phosphates; D012996:Solutions; D014867:Water; D006147:Guanine; D013722:Teprotide; D011683:Purine-Nucleoside Phosphorylase