Crystal structure of human purine nucleoside phosphorylase at 2.3 Å resolution (original) (raw)
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Crystal structure of human purine nucleoside phosphorylase complexed with acyclovir
Biochemical and Biophysical Research Communications, 2003
In human, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. PNP is therefore a target for inhibitor development aiming at Tcell immune response modulation and has been submitted to extensive structure-based drug design. This work reports the first crystallographic study of human PNP complexed with acyclovir (HsPNP:Acy). Acyclovir is a potent clinically useful inhibitor of replicant herpes simplex virus that also inhibits human PNP but with a relatively lower inhibitory activity (K i ¼ 90 lM). Analysis of the structural differences among the HsPNP:Acy complex, PNP apoenzyme, and HsPNP:Immucillin-H provides explanation for inhibitor binding, refines the purine-binding site, and can be used for future inhibitor design.
Biochimie, 2012
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 Å. 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 lM). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions.
Computer-aided rational design of acyclovir analogs to inhibit purine nucleoside phosphorylase
Pharmaceutical and Biomedical Research, 2019
Purine nucleoside phosphorylase (PNP) is one of the major enzymes in the purine salvage pathway. It is responsible for the elevation of deoxyguanosine, and thus considered as the potent target in T-cell lymphoma. The present study examined acyclovir, reported as a low-affinity PNP inhibitor, for the rational design of new acyclovir derivatives by incorporating halogens, hydroxyl, and bulky amino groups. The molecular actions of designed derivatives were investigated by employing density functional theory, molecular docking, and binding energy calculations. The results revealed that the newly designed compounds were highly stable and showed more affinity to PNP than the parent compound, acyclovir. The quantum mechanics and molecular docking studies suggested that modification of side chains with bulky polar groups provided better binding affinities than substitutions with halogens. The resultant derivatives have strong polar interactions like His257 and Tyr88. Furthermore, the design...
Journal of Structural Biology, 2010
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 Å. 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 lM). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions.
Archives of Biochemistry and Biophysics, 2008
Human purine nucleoside phosphorylase (HsPNP) is a target for inhibitor development aiming at T-cell immune response modulation. In this work, we report the development of a new set of empirical scoring functions and its application to evaluate binding affinities and docking results. To test these new functions, we solved the structure of HsPNP and 2-mercapto-4(3H)-quinazolinone (HsPNP:MQU) binary complex at 2.7 Å resolution using synchrotron radiation, and used these functions to predict ligand position obtained in docking simulations. We also employed molecular dynamics simulations to analyze HsPNP in two conditions, as apoenzyme and in the binary complex form, in order to assess the structural features responsible for stability. Analysis of the structural differences between systems provides explanation for inhibitor binding. The use of these scoring functions to evaluate binding affinities and molecular docking results may be used to guide future efforts on virtual screening focused on HsPNP.