Cell
Volume 78, Issue 2, 29 July 1994, Pages 325-334
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Article
The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP

https://doi.org/10.1016/0092-8674(94)90301-8Get rights and content

Abstract

The crystal structure of HGPRTase with bound GMP has been determined and refined to 2.5 Å resolution. The enzyme has a core αβ 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.

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