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'''Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate''' | '''Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate''' | ||
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[[Category: Shi, W.]] | [[Category: Shi, W.]] | ||
[[Category: Tyler, P C.]] | [[Category: Tyler, P C.]] | ||
[[Category: | [[Category: Pnp]] | ||
[[Category: | [[Category: Transition state analogue]] | ||
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Revision as of 07:48, 3 May 2008
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.
About this StructureAbout this Structure
1RR6 is a Single protein structure of sequence from Homo sapiens. 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 Page seeded by OCA on Sat May 3 07:48:45 2008