THE CRYSTAL-STRUCTURE OF HUMAN HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH BOUND GMP

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