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

147 Citations (Scopus)

Abstract

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
Volume6
Issue number6
DOIs
StatePublished - 1999

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Hypoxanthine Phosphoribosyltransferase
Catalytic Domain
Ions
Hydroxyl Radical
Hydrogen
Hydrogen bonds
diphosphoric acid
purine

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Genetics

Cite this

The 2.0 Å structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor. / Shi, Wuxian; Li, Caroline M.; Tyler, Peter C.; Furneaux, Richard H.; Grubmeyer, Charles; Schramm, Vern L.; Almo, Steven C.

In: Nature Structural Biology, Vol. 6, No. 6, 1999, p. 588-593.

Research output: Contribution to journalArticle

Shi, Wuxian ; Li, Caroline M. ; Tyler, Peter C. ; Furneaux, Richard H. ; Grubmeyer, Charles ; Schramm, Vern L. ; Almo, Steven C. / The 2.0 Å structure of human hypoxanthine-guanine phosphoribosyltransferase in complex with a transition-state analog inhibitor. In: Nature Structural Biology. 1999 ; Vol. 6, No. 6. pp. 588-593.
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