5w8v - Revision history

OCA at 14:14, 13 March 2024

OCA — Wed, 13 Mar 2024 14:14:47 GMT

←Older revision		Revision as of 14:14, 13 March 2024
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	==HUMAN HGPRT in complex with [(2-[(guanin-9-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)diphosphonic acid==		==HUMAN HGPRT in complex with [(2-[(guanin-9-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)diphosphonic acid==
-	<StructureSection load='5w8v' size='340' side='right' caption='[[5w8v]], [[Resolution\|resolution]] 2.35Å' scene=''>	+	<StructureSection load='5w8v' size='340' side='right'caption='[[5w8v]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5w8v]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W8V OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5W8V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5w8v]] 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=5W8V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W8V FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9YP:{[(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl}phosphonic+acid'>9YP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene~~></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.346Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9YP:{[(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl}phosphonic+acid'>9YP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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'>[https://proteopedia.org/fgij/fg.htm?mol=5w8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8v OCA], [https://pdbe.org/5w8v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w8v RCSB], [https://www.ebi.ac.uk/pdbsum/5w8v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8v ProSAT]</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=5w8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8v OCA], [~~http~~://pdbe.org/5w8v PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5w8v RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5w8v PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8v ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN]] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[~~http~~://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:[~~http~~://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> [:]	+	[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 ==		== Function ==
-	[~~[http~~://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.	+	[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.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). Based on this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 A resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in low micromolar range in Pf lines and low toxicity in human A549 cells demonstrating that these ANbPs are excellent antimalarial drug leads.	+

-	Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase.,Spacek P, Keough DT, Chavchich M, Dracinsky M, Janeba Z, Naesens L, Edstein MD, Guddat LW, Hockova D J Med Chem. 2017 Aug 16. doi: 10.1021/acs.jmedchem.7b00926. PMID:28813147<ref>PMID:28813147</ref>	+	==See Also==
-		+	*[[Phosphoribosyltransferase 3D structures\|Phosphoribosyltransferase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 5w8v" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Hypoxanthine phosphoribosyltransferase~~]]	+	[[Category: Large Structures]]
-	[[Category: Guddat~~, L W~~]]	+	[[Category: Guddat LW]]
-	[[Category: Keough~~, D T]]~~	+	[[Category: Keough DT]]
-	~~[[Category: 6-oxopurine]]~~	+
-	~~[[Category: Guanine]]~~	+
-	~~[[Category: Hypoxanthine]]~~	+
-	~~[[Category: Nucleoside phosphonate]]~~	+
-	~~[[Category: Phosphoribosyltransferase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 14:44, 6 November 2017

OCA — Mon, 06 Nov 2017 14:44:15 GMT

←Older revision		Revision as of 14:44, 6 November 2017
Line 3:		Line 3:
	<StructureSection load='5w8v' size='340' side='right' caption='[[5w8v]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='5w8v' size='340' side='right' caption='[[5w8v]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5w8v]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W8V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W8V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5w8v]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W8V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W8V FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9YP:{[(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl}phosphonic+acid'>9YP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9YP:{[(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl}phosphonic+acid'>9YP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HPRT1, HPRT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=5w8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8v OCA], [http://pdbe.org/5w8v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w8v RCSB], [http://www.ebi.ac.uk/pdbsum/5w8v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8v ProSAT]</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=5w8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8v OCA], [http://pdbe.org/5w8v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w8v RCSB], [http://www.ebi.ac.uk/pdbsum/5w8v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8v ProSAT]</span></td></tr>
Line 25:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Hypoxanthine phosphoribosyltransferase]]		[[Category: Hypoxanthine phosphoribosyltransferase]]
	[[Category: Guddat, L W]]		[[Category: Guddat, L W]]

OCA: Protected "5w8v" [edit=sysop:move=sysop]

OCA — Wed, 30 Aug 2017 03:55:32 GMT

Protected "5w8v" [edit=sysop:move=sysop]

←Older revision

Revision as of 03:55, 30 August 2017

OCA: New page: ==HUMAN HGPRT in complex with [(2-[(guanin-9-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)diphosphonic acid== == Structural highlights ==
<table><tr><td colspan='2'>[[5w8v]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W8V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W8V FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9YP:{[(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-3-(2-phosphonoethoxy)propoxy]methyl}phosphonic+acid'>9YP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5w8v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w8v OCA], [http://pdbe.org/5w8v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w8v RCSB], [http://www.ebi.ac.uk/pdbsum/5w8v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w8v ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/HPRT_HUMAN HPRT_HUMAN]] Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:[http://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:[http://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 ==
[[http://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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). Based on this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2-phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 A resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in low micromolar range in Pf lines and low toxicity in human A549 cells demonstrating that these ANbPs are excellent antimalarial drug leads.

Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase.,Spacek P, Keough DT, Chavchich M, Dracinsky M, Janeba Z, Naesens L, Edstein MD, Guddat LW, Hockova D J Med Chem. 2017 Aug 16. doi: 10.1021/acs.jmedchem.7b00926. PMID:28813147<ref>PMID:28813147</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5w8v" style="background-color:#fffaf0;"></div>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Hypoxanthine phosphoribosyltransferase]]
[[Category: Guddat, L W]]
[[Category: Keough, D T]]
[[Category: 6-oxopurine]]
[[Category: Guanine]]
[[Category: Hypoxanthine]]
[[Category: Nucleoside phosphonate]]
[[Category: Phosphoribosyltransferase]]
[[Category: Transferase]]