title: The 2.0 A structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor.
abstract: 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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: C M
authors.initials: CM
authors.lastname: Li
authors.forename: P C
authors.initials: PC
authors.lastname: Tyler
authors.forename: R H
authors.initials: RH
authors.lastname: Furneaux
authors.forename: C
authors.initials: C
authors.lastname: Grubmeyer
authors.forename: V L
authors.initials: VL
authors.lastname: Schramm
authors.forename: S C
authors.initials: SC
authors.lastname: Almo
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003460:Crystallization; D018360:Crystallography, X-Ray; D011756:Diphosphates / Q000737:chemistry* / Q000378:metabolism; D004583:Electrons; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D007477:Ions; D008274:Magnesium / Q000378:metabolism; D017616:Magnesium Compounds / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009584:Nitrogen / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011744:Pyrimidinones / Q000737:chemistry* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents
chemical_list: D011756:Diphosphates; D004791:Enzyme Inhibitors; D007477:Ions; D017616:Magnesium Compounds; D010710:Phosphates; D011744:Pyrimidinones; D011758:Pyrroles; D012997:Solvents; C113100:immucillin G; C034732:magnesium pyrophosphate; D007041:Hypoxanthine Phosphoribosyltransferase; D008274:Magnesium; D009584:Nitrogen; D010100:Oxygen