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

Rafael A. Caceres, Luís F S M Timmers, Rodrigo G. Ducati, Diego O N Da Silva, Luiz A. Basso, Walter F. De Azevedo, Diógenes S. Santos

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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:PO 4) at 2.10 resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO 4 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.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalBiochimie
Volume94
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Purine-Nucleoside Phosphorylase
Acyclovir
Molecular Dynamics Simulation
Mycobacterium tuberculosis
Molecular dynamics
Crystal structure
Ligands
Salvaging
Enzymes
Anchors
Drug Design
Phosphates
Binding Sites
Catalytic Domain
Computer simulation

Keywords

  • Acyclovir
  • Crystallographic structure
  • Molecular dynamics
  • Mycobacterium tuberculosis
  • Purine nucleoside phophorylase

ASJC Scopus subject areas

  • Biochemistry

Cite this

Caceres, R. A., Timmers, L. F. S. M., Ducati, R. G., Da Silva, D. O. N., Basso, L. A., De Azevedo, W. F., & Santos, D. S. (2012). Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir. Biochimie, 94(1), 155-165. https://doi.org/10.1016/j.biochi.2011.10.003

Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir. / Caceres, Rafael A.; Timmers, Luís F S M; Ducati, Rodrigo G.; Da Silva, Diego O N; Basso, Luiz A.; De Azevedo, Walter F.; Santos, Diógenes S.

In: Biochimie, Vol. 94, No. 1, 01.2012, p. 155-165.

Research output: Contribution to journalArticle

Caceres, RA, Timmers, LFSM, Ducati, RG, Da Silva, DON, Basso, LA, De Azevedo, WF & Santos, DS 2012, 'Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir', Biochimie, vol. 94, no. 1, pp. 155-165. https://doi.org/10.1016/j.biochi.2011.10.003
Caceres, Rafael A. ; Timmers, Luís F S M ; Ducati, Rodrigo G. ; Da Silva, Diego O N ; Basso, Luiz A. ; De Azevedo, Walter F. ; Santos, Diógenes S. / Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir. In: Biochimie. 2012 ; Vol. 94, No. 1. pp. 155-165.
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