View source for 5hia


==Human hypoxanthine-guanine phosphoribosyltransferase in complex with [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine==
<StructureSection load='5hia' size='340' side='right'caption='[[5hia]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hia]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HIA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.773&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5hia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hia OCA], [https://pdbe.org/5hia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hia RCSB], [https://www.ebi.ac.uk/pdbsum/5hia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hia ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[https://omim.org/entry/300322 300322]. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.<ref>PMID:6853716</ref> <ref>PMID:3384338</ref> <ref>PMID:3265398</ref> <ref>PMID:2910902</ref> <ref>PMID:2347587</ref> <ref>PMID:2358296</ref> <ref>PMID:2246854</ref> <ref>PMID:2071157</ref> <ref>PMID:7627191</ref> <ref>PMID:9452051</ref>   Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:[https://omim.org/entry/300323 300323]; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.<ref>PMID:6853490</ref> <ref>PMID:6572373</ref> <ref>PMID:6706936</ref> <ref>PMID:3358423</ref> <ref>PMID:3198771</ref> <ref>PMID:2909537</ref> [:]
== Function ==
[https://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN] Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
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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.

Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics.,Keough DT, Rejman D, Pohl R, Zbornikova E, Hockova D, Croll T, Edstein MD, Birrell GW, Chavchich M, Naesens LMJ, Pierens GK, Brereton IM, Guddat LW ACS Chem Biol. 2017 Dec 5. doi: 10.1021/acschembio.7b00916. PMID:29161011<ref>PMID:29161011</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5hia" style="background-color:#fffaf0;"></div>

==See Also==
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Guddat LW]]
[[Category: Keough DT]]
[[Category: Rejman D]]