3gep

From Proteopedia

(Difference between revisions)

Current revision

Human hypoxanthine guanine phosphoribosyltranserfase in complex with (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)guanine

Structural highlights

3gep 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 2.6Å
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.

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Wilson JM, Kobayashi R, Fox IH, Kelley WN. Human hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1983 May 25;258(10):6458-60. PMID:6853490
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3gep"

Categories: Homo sapiens | Large Structures | Guddat LW | Jersey J | Keough DT

@@ Line 1: / Line 1: @@
 ==Human hypoxanthine guanine phosphoribosyltranserfase in complex with (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)guanine==
-<StructureSection load='3gep' size='340' side='right' caption='[[3gep]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='3gep' size='340' side='right'caption='[[3gep]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3gep]] is a 2 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=3GEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GEP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3gep]] 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=3GEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GEP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=24H:{[(1S)-2-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-1-(HYDROXYMETHYL)ETHOXY]METHYL}PHOSPHONIC+ACID'>24H</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]] 2.6&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hmp|1hmp]], [[1z7g|1z7g]], [[1d6n|1d6n]], [[1bzy|1bzy]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=24H:{[(1S)-2-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-1-(HYDROXYMETHYL)ETHOXY]METHYL}PHOSPHONIC+ACID'>24H</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HPRT, HPRT1, HPT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3gep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gep OCA], [https://pdbe.org/3gep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gep RCSB], [https://www.ebi.ac.uk/pdbsum/3gep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gep ProSAT]</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=3gep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gep OCA], [http://pdbe.org/3gep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3gep RCSB], [http://www.ebi.ac.uk/pdbsum/3gep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3gep 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> [:]
+[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 ==
-[[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.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 35: / Line 33: @@
 ==See Also==
-*[[Phosphoribosyltransferase|Phosphoribosyltransferase]]
+*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Hypoxanthine phosphoribosyltransferase]]
+[[Category: Large Structures]]
-[[Category: Guddat, L W]]
+[[Category: Guddat LW]]
-[[Category: Jersey, J]]
+[[Category: Jersey J]]
-[[Category: Keough, D T]]
+[[Category: Keough DT]]
-[[Category: Acetylation]]
-[[Category: Acyclic nucleoside phosphonate]]
-[[Category: Cytoplasm]]
-[[Category: Disease mutation]]
-[[Category: Glycosyltransferase]]
-[[Category: Gout]]
-[[Category: Magnesium]]
-[[Category: Malarial chemotherapeutic]]
-[[Category: Metal-binding]]
-[[Category: Phosphoribosyltransferase]]
-[[Category: Purine salvage]]
-[[Category: Purine salvage pathway]]
-[[Category: Transferase]]

3gep

From Proteopedia

Current revision

Human hypoxanthine guanine phosphoribosyltranserfase in complex with (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)guanine

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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