Structural basis for inhibition of human PNP by immucillin-H (original) (raw)

2003, Biochemical and Biophysical Research Communications

Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and de-15 oxynucleosides. PNP is a target for inhibitor development aiming at T-cell immune response modulation. This work reports on the 16 crystallographic study of the complex of human PNP-immucillin-H (HsPNP-ImmH) solved at 2.6 A A resolution using synchrotron 17 radiation. Immucillin-H (ImmH) inhibits the growth of malignant T-cell lines in the presence of deoxyguanosine without affecting 18 non-T-cell tumor lines. ImmH inhibits activated normal human T cells after antigenic stimulation in vitro. These biological effects of 19 ImmH suggest that this agent may have utility in the treatment of certain human diseases characterized by abnormal T-cell growth 20 or activation. This is the first structural report of human PNP complexed with immucillin-H. The comparison of the complex 21 HsPNP-ImmH with recent crystallographic structures of human PNP explains the high specificity of immucillin-H for human PNP. 22