1rr6: Difference between revisions
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[[Image:1rr6.gif|left|200px]]<br /> | [[Image:1rr6.gif|left|200px]]<br /><applet load="1rr6" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1rr6, resolution 2.50Å" /> | caption="1rr6, resolution 2.50Å" /> | ||
'''Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate'''<br /> | '''Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate'''<br /> | ||
==Overview== | ==Overview== | ||
Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an | Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1RR6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PO4 and IMH 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:// | 1RR6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=IMH:'>IMH</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=1RR6 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Purine-nucleoside phosphorylase]] | [[Category: Purine-nucleoside phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Almo, S | [[Category: Almo, S C.]] | ||
[[Category: Furneaux, R | [[Category: Furneaux, R H.]] | ||
[[Category: Lewandowicz, A.]] | [[Category: Lewandowicz, A.]] | ||
[[Category: Schramm, V | [[Category: Schramm, V L.]] | ||
[[Category: Shi, W.]] | [[Category: Shi, W.]] | ||
[[Category: Tyler, P | [[Category: Tyler, P C.]] | ||
[[Category: IMH]] | [[Category: IMH]] | ||
[[Category: PO4]] | [[Category: PO4]] | ||
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[[Category: transition state analogue]] | [[Category: transition state analogue]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:53:43 2008'' | ||
Revision as of 15:53, 21 February 2008
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Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate
OverviewOverview
Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action.
DiseaseDisease
Known diseases associated with this structure: Neutral lipid storage disease with myopathy OMIM:[609059], Nucleoside phosphorylase deficiency, immunodeficiency due to OMIM:[164050]
About this StructureAbout this Structure
1RR6 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Purine-nucleoside phosphorylase, with EC number 2.4.2.1 Full crystallographic information is available from OCA.
ReferenceReference
Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function., Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL, J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926
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