Crystal structure of human PNP complexed with hypoxanthine and sulfate ion

Canduri, Fernanda; Fadel, Valmir; Dias, M.V.B.; Basso, Luiz Augusto; Palma, Mário Sérgio; Santos, Daniel Silas Veras dos; Azevedo, Walter Filgueira de

doi:10.1016/j.bbrc.2004.11.038

Cited by 24 publications

(11 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Enzymatic efficiency of the hSM with adenosine-based prodrugs was further increased when the second mutation of Glu201 to Gln was introduced. Crystal structures of hPNP in complex with either guanosine or inosine indicate that the N1-C2 side of these nucleotides faces Glu201 of hPNP (8, 16, 22). In fact, the carboxyl side chain of Glu201 forms hydrogen bonds with the amino group at C2 in guanosine and with the N1-hydrogen of both guanosine and inosine (16, 18, 21).…”

Section: Discussionmentioning

confidence: 99%

“…hPNP, a ubiquitously expressed homotrimer, catalyzes the reversible phosphorolysis of 6-oxo purine nucleosides to the corresponding free purine base and ribose 1-phosphate, but does not accept adenosine or adenosine-based prodrugs as substrates (8–10). In contrast, homohexameric E. coli PNP (ePNP) efficiently converts adenosine-based prodrugs to adenine containing drugs (11) that can freely diffuse across cell membranes and are toxic to both dividing and non-dividing cells (11–15), including the stromal cells that support tumor growth.…”

Section: Introductionmentioning

confidence: 99%

“…In the present study we have used available crystallographic and enzyme-substrate studies (8–10, 16–22) to rationally design hPNP mutants that can cleave adenosine-based prodrugs not recognized by wild-type hPNP. In particular, a double mutant of hPNP, E201Q:N243D (hDM) that is fused to an A nti- H ER2/ n eu P eptide mimic (23) (AHNP) is able to utilize (deoxy)adenosine-based prodrugs Cladribine, 2-fluoroadenosine, and 2-fluoro-2'-deoxyadenosine as substrates, with the highest enzymatic efficiency seen with 2-fluoro-2'-deoxyadenosine.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Afshar

Asai

Morrison

2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Immunogenicity caused by the use of nonhuman enzymes in antibody-directed enzyme prodrug therapy has limited its clinical application. To overcome this problem, we have developed a mutant human purine nucleoside phosphorylase, which, unlike the wild-type enzyme, accepts (deoxy)adenosine-based prodrugs as substrates. Among the different mutants of human purine nucleoside phosphorylase tested, a double mutant with amino acid substitutions E201Q:N243D (hDM) is the most efficient in cleaving (deoxy)adenosine-based prodrugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Afshar

Asai

Morrison

2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Finally, Canduri et al . [146] reported the crystal structure of human PNP in complex with hypoxanthine and sulfate ion at 2.6 Å resolution. These crystal structures provide information about the location of the binding site of PNP.…”

Section: Application Domainsmentioning

confidence: 99%

Computational Methods for De novo Protein Design and its Applications to the Human Immunodeficiency Virus 1, Purine Nucleoside Phosphorylase, Ubiquitin Specific Protease 7, and Histone Demethylases

Bellows¹,

Floudas²

2010

CDT

View full text Add to dashboard Cite

This paper provides an overview of computational de novo protein design methods, highlighting recent advances and successes. Four protein systems are described that are important targets for drug design: human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. Target areas for drug design for each protein are described, along with known inhibitors, focusing on peptidic inhibitors, but also describing some smallmolecule inhibitors. Computational design methods that have been employed in elucidating these inhibitors for each protein are outlined, along with steps that can be taken in order to apply computational protein design to a system that has mainly used experimental methods to date. KeywordsComputational protein design; human immunodeficiency virus 1; purine nucleoside phosphorylase; ubiquitin specific protease 7; histone demethylases

show abstract

“…shikimate pathway [4][5][6][7][8][9][10][11][12][13][14][15][16], purine pathway [17][18][19][20][21][22][23][24][25][26][27][28][29][30], and CDK9 [31]. shikimate pathway [4][5][6][7][8][9][10][11][12][13][14][15][16], purine pathway [17][18][19][20][21][22][23][24][25][26][27][28]…”

Section: Introductionunclassified

Drug-Binding Databases

Timmers¹,

Pauli²,

Caceres³

et al. 2008

CDT

View full text Add to dashboard Cite

Recent developments in computer power and chemoinformatics methodology make possible that a huge amount of data become available through internet. These databases are devoted to a wide spectrum of scientific fields. Here we are concerned with databases related to protein-drug interactions. More specifically, databases where potential new molecules could be accessed to be used in virtual screening initiatives. In the past decade several databases have been developed where molecules to be used in the virtual screening could be easily identified, downloaded and even purchased. This review describes and summarizes the recent advances in the development of these databases, and also the main applications related to virtual screening projects.

show abstract

Crystal structure of human PNP complexed with hypoxanthine and sulfate ion

Cited by 24 publications

References 18 publications

Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Computational Methods for De novo Protein Design and its Applications to the Human Immunodeficiency Virus 1, Purine Nucleoside Phosphorylase, Ubiquitin Specific Protease 7, and Histone Demethylases

Drug-Binding Databases

Contact Info

Product

Resources

About