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Crystal Structure and Molecular Dynamics Studies of Human Purine Nucleoside Phosphorylase Complexed With 7-deazaguanine

Crystal Structure and Molecular Dynamics Studies of Human Purine Nucleoside Phosphorylase Complexed With 7-deazaguanine

Rafael Andrade Caceres, Luis Fernando Saraiva Macedo Timmers, Ivani Pauli, Lisandra Marques Gava, Rodrigo Gay Ducati, Luiz Augusto Basso, Diógenes Santiago Santos, Walter Filgueira de Azevedo Jr

J Struct Biol. 2010 Mar;169(3):379-88.

PMID: 19932753

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 A. 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 microM). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP26927015	7DG		26927-01-5	Price

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