|1pwy, resolution 2.80Å ()|
|Gene:||PNP (Homo sapiens)|
CRYSTAL STRUCTURE OF HUMAN PNP COMPLEXED WITH ACYCLOVIR
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.
Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir., dos Santos DM, Canduri F, Pereira JH, Vinicius Bertacine Dias M, Silva RG, Mendes MA, Palma MS, Basso LA, de Azevedo WF Jr, Santos DS, Biochem Biophys Res Commun. 2003 Aug 29;308(3):553-9. PMID:12914786
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[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.
About this Structure
- dos Santos DM, Canduri F, Pereira JH, Vinicius Bertacine Dias M, Silva RG, Mendes MA, Palma MS, Basso LA, de Azevedo WF Jr, Santos DS. Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir. Biochem Biophys Res Commun. 2003 Aug 29;308(3):553-9. PMID:12914786
- ↑ Williams SR, Gekeler V, McIvor RS, Martin DW Jr. A human purine nucleoside phosphorylase deficiency caused by a single base change. J Biol Chem. 1987 Feb 15;262(5):2332-8. PMID:3029074
- ↑ Aust MR, Andrews LG, Barrett MJ, Norby-Slycord CJ, Markert ML. Molecular analysis of mutations in a patient with purine nucleoside phosphorylase deficiency. Am J Hum Genet. 1992 Oct;51(4):763-72. PMID:1384322
- ↑ Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K. Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. Hum Genet. 1996 Dec;98(6):706-9. PMID:8931706
- ↑ Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR, Stoeckler JD, Parks RE Jr, et al.. Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution. J Biol Chem. 1990 Jan 25;265(3):1812-20. PMID:2104852