1td1: Difference between revisions

Revision as of 16:12, 21 February 2008

Crystal Structure of the Purine Nucleoside Phosphorylase from Schistosoma mansoni in complex with acetate

OverviewOverview

Despite the availability of effective chemotherapy, schistosomiasis continues to be one of the major parasitic infections to affect the human population worldwide. Currently, little is known of the structural biology of the parasites that are responsible for the disease and few attempts have been made to develop second generation drugs, which may become essential if resistance to those currently available becomes an issue. Here, we describe three crystal structures for the enzyme purine nucleoside phosphorylase (PNP) from Schistosoma mansoni, a component of the purine salvage pathway. PNP is known to be essential for the recovery of purine bases and nucleosides in schistosomes, due to an absence of the enzymes for de novo synthesis, making it a sensitive point in the parasite's metabolism. In all three structures reported here, acetate occupies part of the base-binding site and is directly bound to the conserved glutamic acid at position 203. One of the structures presents the crystallization additive sulfobetaine 195 (NDSB195) occupying simultaneously the ribose and phosphate binding sites, whilst a second presents only phosphate in the latter. The observation of sulfobetaine specifically bound to the protein active site was unexpected and is unique to this structure as far as we are aware. Considerable flexibility is observed in the active site, principally due to variable structural disorder in the regions centered on residues 64 and 260. This conformational plasticity extends to the way in which both NDSB195 and phosphate bind to the individual monomers of the trimeric structure reported here. Differences between the parasite and human enzymes are limited principally to the base-binding site, where the substitution of V245 in the mammalian enzymes by S247 introduces additional hydrogen bonding potential to the site. This is satisfied in the structures described here by a water molecule whose presence is normally observed only in complexes with 6-oxopurines. Residue Y202, which replaces F200 in human PNP, is able to reach over the ribose-binding site to interact with H259 and is predicted to form an additional hydrogen bond with the 5' hydroxyl of nucleoside substrates.

About this StructureAbout this Structure

1TD1 is a Single protein structure of sequence from Schistosoma mansoni with as ligand. Active as Purine-nucleoside phosphorylase, with EC number 2.4.2.1 Full crystallographic information is available from OCA.

ReferenceReference

Structures for the potential drug target purine nucleoside phosphorylase from Schistosoma mansoni causal agent of schistosomiasis., Pereira HD, Franco GR, Cleasby A, Garratt RC, J Mol Biol. 2005 Oct 28;353(3):584-99. Epub 2005 Sep 2. PMID:16182308

Page seeded by OCA on Thu Feb 21 15:12:13 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:1td1.gif|left|200px]]<br /><applet load="1td1" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1td1.gif|left|200px]]<br /><applet load="1td1" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1td1, resolution 1.90&Aring;" />
 '''Crystal Structure of the Purine Nucleoside Phosphorylase from Schistosoma mansoni in complex with acetate'''<br />
 ==Overview==
-Despite the availability of effective chemotherapy, schistosomiasis, continues to be one of the major parasitic infections to affect the human, population worldwide. Currently, little is known of the structural biology, of the parasites that are responsible for the disease and few attempts, have been made to develop second generation drugs, which may become, essential if resistance to those currently available becomes an issue., Here, we describe three crystal structures for the enzyme purine, nucleoside phosphorylase (PNP) from Schistosoma mansoni, a component of, the purine salvage pathway. PNP is known to be essential for the recovery, of purine bases and nucleosides in schistosomes, due to an absence of the, enzymes for de novo synthesis, making it a sensitive point in the, parasite's metabolism. In all three structures reported here, acetate, occupies part of the base-binding site and is directly bound to the, conserved glutamic acid at position 203. One of the structures presents, the crystallization additive sulfobetaine 195 (NDSB195) occupying, simultaneously the ribose and phosphate binding sites, whilst a second, presents only phosphate in the latter. The observation of sulfobetaine, specifically bound to the protein active site was unexpected and is unique, to this structure as far as we are aware. Considerable flexibility is, observed in the active site, principally due to variable structural, disorder in the regions centered on residues 64 and 260. This, conformational plasticity extends to the way in which both NDSB195 and, phosphate bind to the individual monomers of the trimeric structure, reported here. Differences between the parasite and human enzymes are, limited principally to the base-binding site, where the substitution of, V245 in the mammalian enzymes by S247 introduces additional hydrogen, bonding potential to the site. This is satisfied in the structures, described here by a water molecule whose presence is normally observed, only in complexes with 6-oxopurines. Residue Y202, which replaces F200 in, human PNP, is able to reach over the ribose-binding site to interact with, H259 and is predicted to form an additional hydrogen bond with the 5', hydroxyl of nucleoside substrates.
+Despite the availability of effective chemotherapy, schistosomiasis continues to be one of the major parasitic infections to affect the human population worldwide. Currently, little is known of the structural biology of the parasites that are responsible for the disease and few attempts have been made to develop second generation drugs, which may become essential if resistance to those currently available becomes an issue. Here, we describe three crystal structures for the enzyme purine nucleoside phosphorylase (PNP) from Schistosoma mansoni, a component of the purine salvage pathway. PNP is known to be essential for the recovery of purine bases and nucleosides in schistosomes, due to an absence of the enzymes for de novo synthesis, making it a sensitive point in the parasite's metabolism. In all three structures reported here, acetate occupies part of the base-binding site and is directly bound to the conserved glutamic acid at position 203. One of the structures presents the crystallization additive sulfobetaine 195 (NDSB195) occupying simultaneously the ribose and phosphate binding sites, whilst a second presents only phosphate in the latter. The observation of sulfobetaine specifically bound to the protein active site was unexpected and is unique to this structure as far as we are aware. Considerable flexibility is observed in the active site, principally due to variable structural disorder in the regions centered on residues 64 and 260. This conformational plasticity extends to the way in which both NDSB195 and phosphate bind to the individual monomers of the trimeric structure reported here. Differences between the parasite and human enzymes are limited principally to the base-binding site, where the substitution of V245 in the mammalian enzymes by S247 introduces additional hydrogen bonding potential to the site. This is satisfied in the structures described here by a water molecule whose presence is normally observed only in complexes with 6-oxopurines. Residue Y202, which replaces F200 in human PNP, is able to reach over the ribose-binding site to interact with H259 and is predicted to form an additional hydrogen bond with the 5' hydroxyl of nucleoside substrates.
 ==About this Structure==
-TD1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni] with ACT as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1TD1 OCA].
+TD1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni] with <scene name='pdbligand=ACT:'>ACT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1TD1 OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Cleasby, A.]]
-[[Category: Franco, G.R.]]
+[[Category: Franco, G R.]]
-[[Category: Garratt, R.C.]]
+[[Category: Garratt, R C.]]
-[[Category: Pereira, H.D.]]
+[[Category: Pereira, H D.]]
 [[Category: ACT]]
 [[Category: purine nucleoside phosphorylase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 02:02:04 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:12:13 2008''