1oty: Difference between revisions

Revision as of 15:21, 21 February 2008

Native PNP +ALLO

OverviewOverview

Activation of prodrugs by Escherichia coli purine nucleoside phosphorylase (PNP) provides a method for selectively killing tumor cells expressing a transfected PNP gene. This gene therapy approach requires matching a prodrug and a known enzymatic activity present only in tumor cells. The specificity of the method relies on avoiding prodrug cleavage by enzymes already present in the host cells or the intestinal flora. Using crystallographic and computer modeling methods as guides, we have redesigned E. coli PNP to cleave new prodrug substrates more efficiently than does the wild-type enzyme. In particular, the M64V PNP mutant cleaves 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine with a kcat/Km over 100 times greater than for native E. coli PNP. In a xenograft tumor experiment, this compound caused regression of tumors expressing the M64V PNP gene.

About this StructureAbout this Structure

1OTY is a Single protein structure of sequence from Escherichia coli with and as ligands. Active as Purine-nucleoside phosphorylase, with EC number 2.4.2.1 Full crystallographic information is available from OCA.

ReferenceReference

Designer gene therapy using an Escherichia coli purine nucleoside phosphorylase/prodrug system., Bennett EM, Anand R, Allan PW, Hassan AE, Hong JS, Levasseur DN, McPherson DT, Parker WB, Secrist JA 3rd, Sorscher EJ, Townes TM, Waud WR, Ealick SE, Chem Biol. 2003 Dec;10(12):1173-81. PMID:14700625

Page seeded by OCA on Thu Feb 21 14:21:31 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1oty.jpg|left|200px]]<br /><applet load="1oty" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1oty.jpg|left|200px]]<br /><applet load="1oty" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1oty, resolution 2.50&Aring;" />
 '''Native PNP +ALLO'''<br />
 ==Overview==
-Activation of prodrugs by Escherichia coli purine nucleoside phosphorylase, (PNP) provides a method for selectively killing tumor cells expressing a, transfected PNP gene. This gene therapy approach requires matching a, prodrug and a known enzymatic activity present only in tumor cells. The, specificity of the method relies on avoiding prodrug cleavage by enzymes, already present in the host cells or the intestinal flora. Using, crystallographic and computer modeling methods as guides, we have, redesigned E. coli PNP to cleave new prodrug substrates more efficiently, than does the wild-type enzyme. In particular, the M64V PNP mutant cleaves, 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine with a kcat/Km over 100, times greater than for native E. coli PNP. In a xenograft tumor, experiment, this compound caused regression of tumors expressing the M64V, PNP gene.
+Activation of prodrugs by Escherichia coli purine nucleoside phosphorylase (PNP) provides a method for selectively killing tumor cells expressing a transfected PNP gene. This gene therapy approach requires matching a prodrug and a known enzymatic activity present only in tumor cells. The specificity of the method relies on avoiding prodrug cleavage by enzymes already present in the host cells or the intestinal flora. Using crystallographic and computer modeling methods as guides, we have redesigned E. coli PNP to cleave new prodrug substrates more efficiently than does the wild-type enzyme. In particular, the M64V PNP mutant cleaves 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine with a kcat/Km over 100 times greater than for native E. coli PNP. In a xenograft tumor experiment, this compound caused regression of tumors expressing the M64V PNP gene.
 ==About this Structure==
-OTY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with PO4 and 6MP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OTY OCA].
+OTY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=6MP:'>6MP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OTY OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Purine-nucleoside phosphorylase]]
 [[Category: Single protein]]
-[[Category: Allan, P.W.]]
+[[Category: Allan, P W.]]
 [[Category: Anand, R.]]
-[[Category: Bennett, E.M.]]
+[[Category: Bennett, E M.]]
-[[Category: Ealick, S.E.]]
+[[Category: Ealick, S E.]]
-[[Category: Hassan, A.E.]]
+[[Category: Hassan, A E.]]
-[[Category: McPherson, D.T.]]
+[[Category: McPherson, D T.]]
-[[Category: Parker, W.B.]]
+[[Category: Parker, W B.]]
-[[Category: Secrist, J.A.]]
+[[Category: Secrist, J A.]]
-[[Category: Sorscher, E.J.]]
+[[Category: Sorscher, E J.]]
 [[Category: 6MP]]
 [[Category: PO4]]
 [[Category: glycosyltransferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 23:12:15 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:21:31 2008''