Structural basis for inhibition of human PNP by immucillin-H |
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Authors: | Filgueira de Azevedo Walter Canduri Fernanda Marangoni dos Santos Denis Pereira José Henrique Dias Márcio Vinicius Bertacine Silva Rafael Guimarães Mendes Maria Anita Basso Luiz Augusto Palma Mário Sérgio Santos Diógenes Santiago |
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Institution: | Departamento de Física, UNESP, S?o José do Rio Preto, SP 15054-000, Brazil. walterfa@df.ibilce.unesp.br |
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Abstract: | 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. This work reports on the crystallographic study of the complex of human PNP-immucillin-H (HsPNP-ImmH) solved at 2.6A resolution using synchrotron radiation. Immucillin-H (ImmH) inhibits the growth of malignant T-cell lines in the presence of deoxyguanosine without affecting non-T-cell tumor lines. ImmH inhibits activated normal human T cells after antigenic stimulation in vitro. These biological effects of ImmH suggest that this agent may have utility in the treatment of certain human diseases characterized by abnormal T-cell growth or activation. This is the first structural report of human PNP complexed with immucillin-H. The comparison of the complex HsPNP-ImmH with recent crystallographic structures of human PNP explains the high specificity of immucillin-H for human PNP. |
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Keywords: | PNP Synchrotron radiation Structure Immucillin-H Drug design |
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