Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir

被引:14
|
作者
Caceres, Rafael A. [1 ,2 ]
Timmers, Luis F. S. M. [1 ,3 ]
Ducati, Rodrigo G. [4 ]
da Silva, Diego O. N. [5 ]
Basso, Luiz A. [2 ,3 ,4 ]
de Azevedo, Walter F., Jr. [1 ,2 ,3 ]
Santos, Diogenes S. [2 ,3 ,4 ]
机构
[1] Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, Lab Bioquim Estrutural, Porto Alegre, RS, Brazil
[2] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Med & Ciencias Saude, Porto Alegre, RS, Brazil
[3] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Biol Celular & Mol, Porto Alegre, RS, Brazil
[4] Pontificia Univ Catolica Rio Grande do Sul, Ctr Pesquisas Biol Mol & Func CPBMF, Inst Pesquisas Biomed, Porto Alegre, RS, Brazil
[5] Univ Catolica Brasilia, Brasilia, DF, Brazil
关键词
Purine nucleoside phophorylase; Mycobacterium tuberculosis; Crystallographic structure; Acyclovir; Molecular dynamics; ESCHERICHIA-COLI; PNP; MECHANISM; PROGRAM; DOCKING;
D O I
10.1016/j.biochi.2011.10.003
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
Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO4) at 2.10 angstrom resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO4 structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K-i = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible. (C) 2011 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:155 / 165
页数:11
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