6bo7

<StructureSection load='6bo7' size='340' side='right' caption='[[6bo7]], [[Resolution|resolution]] 2.86&Aring;' scene=''>

<table><tr><td colspan='2'>[[6bo7]] is a 12 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5hhu 5hhu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BO7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BO7 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=YPG:[3-[(3~{R},4~{R})-3-(2-AZANYL-6-OXIDANYLIDENE-1~{H}-PURIN-9-YL)-4-[(2~{S})-2-OXIDANYL-2-PHOSPHONO-ETHOXY]PYRROLIDIN-1-YL]-3-OXIDANYLIDENE-PROPYL]PHOSPHONIC+ACID'>YPG</scene></td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hypoxanthine_phosphoribosyltransferase Hypoxanthine phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.8 2.4.2.8] </span></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bo7 OCA], [http://pdbe.org/6bo7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bo7 RCSB], [http://www.ebi.ac.uk/pdbsum/6bo7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bo7 ProSAT]</span></td></tr>

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== Publication Abstract from PubMed ==

Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropion yl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 A resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 +/- 3.2 muM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 +/- 11 muM, thus giving it a approximately 10-fold selectivity index.

 

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== References ==

[[Category: Hypoxanthine phosphoribosyltransferase]]

[[Category: Guddat, L W]]

[[Category: Keough, D T]]

[[Category: Rejman, D]]

[[Category: Complex]]

[[Category: Transferase-inhibitor complex]]