The 2.0 angstrom structure of human hypoxanthineguanine phosphoribosyltransferase in complex with a transition-state analog inhibitor

The structure of human HGPRT bound to the transition-state analog immucilli nGP and Mg2+-pyrophosphate has been determined to 2.0 Angstrom resolution. ImmucillinGP was designed as a stable analog with the stereoelectronic feat ures of the transition state. Bound inhibitor at the catalytic site indicat es that the oxocarbenium ion of the transition state is stabilized by neigh boring-group participation from MgPPi and O5'. A short hydrogen bond forms between Asp 137 and the purine ring analog. Two Mg2+ ions sandwich the pyro phosphate and contact both hydroxyls of the ribosyl analog. The transition- state analog is shielded from bulk solvent by a catalytic loop that moves s imilar to 25 Angstrom to cover the active site and becomes an ordered antip arallel beta-sheet.