3ggc: Difference between revisions

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<StructureSection load='3ggc' size='340' side='right'caption='[[3ggc]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
<StructureSection load='3ggc' size='340' side='right'caption='[[3ggc]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3ggc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GGC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GGC FirstGlance]. <br>
<table><tr><td colspan='2'>[[3ggc]] is a 2 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=3GGC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GGC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H26:{2-[2-(6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)ETHOXY]ETHYL}PHOSPHONIC+ACID'>H26</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]] 2.78&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hmp|1hmp]], [[1z7g|1z7g]], [[1d6n|1d6n]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H26:{2-[2-(6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)ETHOXY]ETHYL}PHOSPHONIC+ACID'>H26</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HPRT, HPRT1, HPT ([https://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'>[https://en.wikipedia.org/wiki/Hypoxanthine_phosphoribosyltransferase Hypoxanthine phosphoribosyltransferase], with EC number [https://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=3ggc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ggc OCA], [https://pdbe.org/3ggc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ggc RCSB], [https://www.ebi.ac.uk/pdbsum/3ggc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ggc ProSAT]</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=3ggc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ggc OCA], [https://pdbe.org/3ggc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ggc RCSB], [https://www.ebi.ac.uk/pdbsum/3ggc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ggc ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== 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> [:]  
[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 ==
[[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.  
[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.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Hypoxanthine phosphoribosyltransferase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Guddat, L W]]
[[Category: Guddat LW]]
[[Category: Jersey, J]]
[[Category: Jersey J]]
[[Category: Keough, D T]]
[[Category: Keough DT]]
[[Category: Acyclic nucleoside phosphonate]]
[[Category: Disease mutation]]
[[Category: Glycosyltransferase]]
[[Category: Gout]]
[[Category: Magnesium]]
[[Category: Metal-binding]]
[[Category: Phosphoribosyltransferase]]
[[Category: Purine salvage]]
[[Category: Transferase]]

Latest revision as of 18:39, 1 November 2023

Human hypoxanthine-guanine phosphoribosyltransferase in complex with 9-(2-phosphonoethoxyethyl)hypoxanthineHuman hypoxanthine-guanine phosphoribosyltransferase in complex with 9-(2-phosphonoethoxyethyl)hypoxanthine

Structural highlights

3ggc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.78Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HPRT_HUMAN Defects in HPRT1 are the cause of Lesch-Nyhan syndrome (LNS) [MIM:300322. LNS is characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self-mutilation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in HPRT1 are the cause of gout HPRT-related (GOUT-HPRT) [MIM:300323; also known as HPRT-related gout or Kelley-Seegmiller syndrome. Gout is characterized by partial enzyme activity and hyperuricemia.[11] [12] [13] [14] [15] [16] [:]

Function

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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite, Plasmodium falciparum. Acyclic nucleoside phosphonates (ANPs) are analogues of the nucleotide product of the reaction, comprising a purine base joined by a linker to a phosphonate moiety. K(i) values for 19 ANPs were determined for Pf HGXPRT and the corresponding human enzyme, HGPRT. Values for Pf HGXPRT were as low as 100 nM, with selectivity for the parasite enzyme of up to 58. Structures of human HGPRT in complex with three ANPs are reported. On binding, a large mobile loop in the free enzyme moves to partly cover the active site. For three ANPs, the IC(50) values for Pf grown in cell culture were 1, 14, and 46 microM, while the cytotoxic concentration for the first compound was 489 microM. These results provide a basis for the design of potent and selective ANP inhibitors of Pf HGXPRT as antimalarial drug leads.

Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics.,Keough DT, Hockova D, Holy A, Naesens LM, Skinner-Adams TS, Jersey J, Guddat LW J Med Chem. 2009 Jul 23;52(14):4391-9. PMID:19527031[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Wilson JM, Kelley WN. Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome. J Clin Invest. 1983 May;71(5):1331-5. PMID:6853716
  2. ↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Genetic basis of hypoxanthine guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome (HPRTFlint). Gene. 1988 Mar 31;63(2):331-6. PMID:3384338
  3. ↑ Davidson BL, Palella TD, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase: a single nucleotide substitution in cDNA clones isolated from a patient with Lesch-Nyhan syndrome (HPRTMidland). Gene. 1988 Aug 15;68(1):85-91. PMID:3265398
  4. ↑ Fujimori S, Davidson BL, Kelley WN, Palella TD. Identification of a single nucleotide change in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRTYale) responsible for Lesch-Nyhan syndrome. J Clin Invest. 1989 Jan;83(1):11-3. PMID:2910902 doi:http://dx.doi.org/10.1172/JCI113846
  5. ↑ Gibbs RA, Nguyen PN, Edwards A, Civitello AB, Caskey CT. Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics. 1990 Jun;7(2):235-44. PMID:2347587
  6. ↑ Skopek TR, Recio L, Simpson D, Dallaire L, Melancon SB, Ogier H, O'Neill JP, Falta MT, Nicklas JA, Albertini RJ. Molecular analyses of a Lesch-Nyhan syndrome mutation (hprtMontreal) by use of T-lymphocyte cultures. Hum Genet. 1990 Jun;85(1):111-6. PMID:2358296
  7. ↑ Gordon RB, Sculley DG, Dawson PA, Beacham IR, Emmerson BT. Identification of a single nucleotide substitution in the coding sequence of in vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBRISBANE). J Inherit Metab Dis. 1990;13(5):692-700. PMID:2246854
  8. ↑ Tarle SA, Davidson BL, Wu VC, Zidar FJ, Seegmiller JE, Kelley WN, Palella TD. Determination of the mutations responsible for the Lesch-Nyhan syndrome in 17 subjects. Genomics. 1991 Jun;10(2):499-501. PMID:2071157
  9. ↑ Burgemeister R, Rotzer E, Gutensohn W, Gehrke M, Schiel W. Identification of a new missense mutation in exon 2 of the human hypoxanthine phosphoribosyltransferase gene (HPRTIsar): a further example of clinical heterogeneity in HPRT deficiencies. Hum Mutat. 1995;5(4):341-4. PMID:7627191 doi:http://dx.doi.org/10.1002/humu.1380050413
  10. ↑ Liu G, Aral B, Zabot MT, Kamoun P, Ceballos-Picot I. The molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in French families; report of two novel mutations. Hum Mutat. 1998;Suppl 1:S88-90. PMID:9452051
  11. ↑ Wilson JM, Kobayashi R, Fox IH, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1983 May 25;258(10):6458-60. PMID:6853490
  12. ↑ Wilson JM, Tarr GE, Kelley WN. Human hypoxanthine (guanine) phosphoribosyltransferase: an amino acid substitution in a mutant form of the enzyme isolated from a patient with gout. Proc Natl Acad Sci U S A. 1983 Feb;80(3):870-3. PMID:6572373
  13. ↑ Wilson JM, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. Structural alteration in a dysfunctional enzyme variant (HPRTMunich) isolated from a patient with gout. J Biol Chem. 1984 Jan 10;259(1):27-30. PMID:6706936
  14. ↑ Cariello NF, Scott JK, Kat AG, Thilly WG, Keohavong P. Resolution of a missense mutant in human genomic DNA by denaturing gradient gel electrophoresis and direct sequencing using in vitro DNA amplification: HPRT Munich. Am J Hum Genet. 1988 May;42(5):726-34. PMID:3358423
  15. ↑ Davidson BL, Chin SJ, Wilson JM, Kelley WN, Palella TD. Hypoxanthine-guanine phosphoribosyltransferase. Genetic evidence for identical mutations in two partially deficient subjects. J Clin Invest. 1988 Dec;82(6):2164-7. PMID:3198771 doi:http://dx.doi.org/10.1172/JCI113839
  16. ↑ Davidson BL, Pashmforoush M, Kelley WN, Palella TD. Human hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular defect in a patient with gout (HPRTAshville). J Biol Chem. 1989 Jan 5;264(1):520-5. PMID:2909537
  17. ↑ Keough DT, Hockova D, Holy A, Naesens LM, Skinner-Adams TS, Jersey J, Guddat LW. Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics. J Med Chem. 2009 Jul 23;52(14):4391-9. PMID:19527031 doi:10.1021/jm900267n

3ggc, resolution 2.78Å

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