1q1g

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{{STRUCTURE_1q1g| PDB=1q1g | SCENE= }}
{{STRUCTURE_1q1g| PDB=1q1g | SCENE= }}
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'''Crystal structure of Plasmodium falciparum PNP with 5'-methylthio-immucillin-H'''
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===Crystal structure of Plasmodium falciparum PNP with 5'-methylthio-immucillin-H===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_14982926}}
==About this Structure==
==About this Structure==
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[[Category: Tyler, P C.]]
[[Category: Tyler, P C.]]
[[Category: Transition state complex]]
[[Category: Transition state complex]]
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Revision as of 01:08, 29 July 2008

Image:1q1g.png

Template:STRUCTURE 1q1g

Crystal structure of Plasmodium falciparum PNP with 5'-methylthio-immucillin-H

Template:ABSTRACT PUBMED 14982926

About this Structure

1Q1G is a Single protein structure of sequence from Plasmodium falciparum 3d7. Full crystallographic information is available from OCA.

Reference

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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