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. doi: 10.1038/9376.

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.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Crystallization
  • Crystallography, X-Ray
  • Diphosphates / chemistry*
  • Diphosphates / metabolism
  • Electrons
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrogen Bonding
  • Hypoxanthine Phosphoribosyltransferase / antagonists & inhibitors
  • Hypoxanthine Phosphoribosyltransferase / chemistry*
  • Hypoxanthine Phosphoribosyltransferase / metabolism
  • Ions
  • Magnesium / metabolism
  • Magnesium Compounds / chemistry*
  • Magnesium Compounds / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Nitrogen / metabolism
  • Oxygen / metabolism
  • Phosphates / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Pyrimidinones / chemistry*
  • Pyrimidinones / metabolism
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Solvents

Substances

  • Diphosphates
  • Enzyme Inhibitors
  • Ions
  • Magnesium Compounds
  • Phosphates
  • Pyrimidinones
  • Pyrroles
  • Solvents
  • immucillin G
  • magnesium pyrophosphate
  • Hypoxanthine Phosphoribosyltransferase
  • Magnesium
  • Nitrogen
  • Oxygen

Associated data

  • PDB/1BZY