Guanylate kinase (EC 2.7.4.8) (GK) [1] catalyzes the ATP-dependent phosphorylation of GMP into GDP. It is essential for recycling GMP and indirectly, cGMP. In prokaryotes (such as Escherichia coli), lower eukaryotes (such as yeast) and in vertebrates, GK is a highly conserved monomeric protein of about 200 amino acids. GK has been shown [2,3,4] to be structurally similar to the following proteins:

• Protein A57R (or SalG2R) from various strains of Vaccinia virus. This protein is highly similar to GK, but contains a frameshift mutation in the N-terminal section and could therefore be inactive in that virus.

The following proteins are characterized by the presence in their sequence of one or more copies of the DHR domain, a SH3 domain (see <PDOC50002> as well as a C-terminal GK-like domain, these protein are collectively termed MAGUKs (membrane-associated guanylate kinase homologs) [5]:

• Drosophila lethal(1)discs large-1 tumor suppressor protein (gene dlg1). This protein is associated with septate junctions in developing flies and defects in the dlg1 gene cause neoplastic overgrowth of the imaginal disks.
• Mammalian tight junction protein Zo-1.
• A family of mammalian synaptic proteins that seem to interact with the cytoplasmic tail of NMDA receptor subunits. This familly currently consist of SAP90/PSD-95, CHAPSYN-110/PSD-93, SAP97/DLG1 and SAP102.
• Vertebrate 55 Kd erythrocyte membrane protein (p55). p55 is a palmitoylated, membrane-associated protein of unknown function.
• Caenorhabditis elegans protein lin-2, which may play a structural role in the induction of the vulva.
• Rat protein CASK.
• Human protein DLG2.
• Human protein DLG3.

There is an ATP-binding site (P-loop) in the N-terminal section of GK. This region is not conserved in the GK-like domain of the above proteins which are therefore unlikely to be kinases. However these proteins retain the residues known, in GK, to be involved in the binding of GMP. As a signature pattern we selected a highly conserved region that contains two arginine and a tyrosine which are involved in GMP-binding.