The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP

Cell. 1994 Jul 29;78(2):325-34. doi: 10.1016/0092-8674(94)90301-8.

Abstract

The crystal structure of HGPRTase with bound GMP has been determined and refined to 2.5 A resolution. The enzyme has a core alpha/beta structure resembling the nucleotide-binding fold of dehydrogenases, and a second lobe composed of residues from the amino and carboxy termini. The GMP molecule binds in an anti conformation in a solvent-exposed cleft of the enzyme. Lys-165, which forms a hydrogen bond to O6 of GMP, appears to be critical for determining the specificity for guanine and hypoxanthine over adenine. The location of active site residues also provides evidence for a possible mechanism for general base-assisted HGPRTase catalysis. A rationalization of the effects on stability and activity of naturally occurring single amino acid mutations of HGPRTase is presented, including a discussion of several mutations at the active site that lead to Lesch-Nyhan syndrome.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography
  • Crystallography, X-Ray
  • Guanosine Monophosphate / metabolism*
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / chemistry*
  • Hypoxanthine Phosphoribosyltransferase / isolation & purification
  • Hypoxanthine Phosphoribosyltransferase / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation / genetics
  • Protein Conformation*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism

Substances

  • Recombinant Proteins
  • Guanosine Monophosphate
  • Hypoxanthine Phosphoribosyltransferase