The 2.0 Å structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor

The structure of human HGPRT bound to the transition-state analog immucillinGP and Mg²⁺-pyrophosphate has been determined to 2.0 Å 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 MgPP(i) 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 ~25 Å to cover the active site and becomes an ordered antiparallel β-sheet.