Structural basis for inhibition of human PNP by immucillin-H

被引：44

作者：

de Azevedo, WF ^{[1
]}

Canduri, F

dos Santos, DM

Pereira, JH

Dias, MVB

Silva, RG

Mendes, MA

Basso, LA

Palma, MS

Santosce, DS

机构：

[1] UNESP, Dept Fis, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil

[2] Inst Butantan, Ctr Appl Toxinol, BR-05503900 Sao Paulo, Brazil

[3] Univ Fed Rio Grande do Sul, Dept Biol Mol & Biotecnol, Rede Brasileira Pesquisas TB, BR-91501970 Porto Alegre, RS, Brazil

[4] UNESP, Inst Biosci, Dept Biol, CEIS,Lab Struct Biol & Zoochem, BR-13506900 Rio Claro, SP, Brazil

[5] Pontificia Univ Catolica Rio Grande do Sul, Inst Pesquisas Biomed, Fac Farm, Porto Alegre, RS, Brazil

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2003年 / 309卷 / 04期

基金：

巴西圣保罗研究基金会;

关键词：

PNP; synchrotron radiation; structure; immucillin-H; drug design;

D O I：

10.1016/j.bbrc.2003.08.094

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 2.6 Angstrom 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. (C) 2003 Elsevier Inc. All rights reserved.

引用

页码：917 / 922

页数：6

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