title: The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP.
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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: J C
authors.initials: JC
authors.lastname: Eads
authors.forename: G
authors.initials: G
authors.lastname: Scapin
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: C
authors.initials: C
authors.lastname: Grubmeyer
authors.forename: J C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003461:Crystallography; D018360:Crystallography, X-Ray; D006157:Guanosine Monophosphate / Q000378:metabolism*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D006157:Guanosine Monophosphate; D007041:Hypoxanthine Phosphoribosyltransferase