Crystal structure of human purine nucleoside phosphorylase in complex with 7-deazaguanine
[PNPH_HUMAN] Defects in PNP are the cause of purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179]. It leads to a severe T-cell immunodeficiency with neurologic disorder in children.  
[PNPH_HUMAN] The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
Publication Abstract from PubMed
In humans, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. HsPNP is a target for inhibitor development aiming at T-cell immune response modulation. Here we report the crystal structure of HsPNP in complex with 7-deazaguanine (HsPNP:7DG) at 2.75 A. Molecular dynamics simulations were employed to assess the structural features of HsPNP in both free form and in complex with 7DG. Our results show that some regions, responsible for entrance and exit of substrate, present a conformational variability, which is dissected by dynamics simulation analysis. Enzymatic assays were also carried out and revealed that 7-deazaguanine presents a lower inhibitory activity against HsPNP (K(i)=200 microM). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions.
Crystal structure and molecular dynamics studies of human purine nucleoside phosphorylase complexed with 7-deazaguanine.,Caceres RA, Timmers LF, Pauli I, Gava LM, Ducati RG, Basso LA, Santos DS, de Azevedo WF Jr J Struct Biol. 2010 Mar;169(3):379-88. Epub 2009 Nov 22. PMID:19932753
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.