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Type: Artigo de periódico
Title: Crystal structure and molecular dynamics studies of human purine nucleoside phosphorylase complexed with 7-deazaguanine
Author: Caceres, RA
Timmers, LFSM
Pauli, I
Gava, LM
Ducati, RG
Basso, LA
Santos, DS
de Azevedo, WF
Abstract: 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 angstrom. 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 mu M). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions. (C) 2009 Elsevier Inc. All rights reserved.
Subject: Purine nucleoside phosphorylase
Molecular dynamics
Virtual screening
X-ray diffraction
Enzymatic assay
Country: EUA
Editor: Academic Press Inc Elsevier Science
Citation: Journal Of Structural Biology. Academic Press Inc Elsevier Science, v. 169, n. 3, n. 379, n. 388, 2010.
Rights: fechado
Identifier DOI: 10.1016/j.jsb.2009.11.010
Date Issue: 2010
Appears in Collections:Unicamp - Artigos e Outros Documentos

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