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

Wuxian Shi, Caroline M. Li, Peter C. Tyler, Richard H. Furneaux, Charles Grubmeyer, Vern L. Schramm, Steven C. Almo

Research output: Contribution to journalArticle

150 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)588-593
Number of pages6
JournalNature structural biology
Issue number6
StatePublished - Jun 9 1999


ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

Cite this