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Publication Abstract from PubMed

Guanine monophosphate (GMP) synthetase is a bifunctional two domain enzyme. The N-terminal glutaminase domain generates ammonia from glutamine and the C-terminal synthetase domain aminates xanthine monophosphate (XMP) to form GMP. Mammalian GMP synthetases contain a 130 residues long insert in the synthetase domain in comparison to bacterial proteins. We report here the structure of an eukaryotic GMP synthetase. Substrate XMP was bound in the crystal structure of the human GMP synthetase enzyme. XMP is bound to the synthetase domain and covered by a LID motif. The enzyme forms a dimer in the crystal structure with entirely different subunit orientations than the bacterial counterparts. The inserted sub-domain is shown to be involved in substrate binding and dimerization. Furthermore, the structural basis for XMP recognition is revealed as well as a potential allosteric site. Enzymes in the nucleotide metabolism typically display an increased activity in proliferating cells due to the increased need for nucleotides. Many drugs used as immunosuppressants and for treatment of cancer and viral diseases are indeed nucleobase- and nucleoside-based compounds, which are acting on or are activated by enzymes in this pathway. The information obtained from the crystal structure of human GMP synthetase might therefore aid in understanding interactions of nucleoside based drugs with GMP synthetase and in structure-based design of GMP synthetase specific inhibitors.

Substrate Specificity and Oligomerization of Human GMP Synthetase.,Welin M, Lehtio L, Johansson A, Flodin S, Nyman T, Tresaugues L, Hammarstrom M, Graslund S, Nordlund P J Mol Biol. 2013 Jun 28. pii: S0022-2836(13)00427-0. doi:, 10.1016/j.jmb.2013.06.032. PMID:23816837^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.