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|1bzy, resolution 2.00Å ()|
HUMAN HGPRTASE WITH TRANSITION STATE INHIBITOR
The structure of human HGPRT bound to the transition-state analog immucillinGP and Mg2+-pyrophosphate has been determined to 2.0 A resolution. ImmucillinGP was designed as a stable analog with the stereoelectronic features of the transition state. Bound inhibitor at the catalytic site indicates that the oxocarbenium ion of the transition state is stabilized by neighboring-group participation from MgPPi and O5'. A short hydrogen bond forms between Asp 137 and the purine ring analog. Two Mg2+ ions sandwich the pyrophosphate and contact both hydroxyls of the ribosyl analog. The transition-state analog is shielded from bulk solvent by a catalytic loop that moves approximately 25 A to cover the active site and becomes an ordered antiparallel beta-sheet.
The 2.0 A structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor., Shi W, Li CM, Tyler PC, Furneaux RH, Grubmeyer C, Schramm VL, Almo SC, Nat Struct Biol. 1999 Jun;6(6):588-93. PMID:10360366
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[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. 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.[:]
[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.
About this Structure
- Shi W, Li CM, Tyler PC, Furneaux RH, Grubmeyer C, Schramm VL, Almo SC. The 2.0 A structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor. Nat Struct Biol. 1999 Jun;6(6):588-93. PMID:10360366 doi:http://dx.doi.org/10.1038/9376
- ↑ 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