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The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase

DOI: 10.1186/1472-6807-8-42

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We have determined the crystal structure of the catalytic domain of a soluble guanylate cyclase from the green algae Chlamydomonas reinhardtii at 2.55 ? resolution, and show that it is a dimeric molecule.Comparison of the structure of the guanylate cyclase domain with the known structures of adenylate cyclases confirms the close similarity in architecture between these two enzymes, as expected from their sequence similarity. The comparison also suggests that the crystallized guanylate cyclase is in an inactive conformation, and the structure provides indications as to how activation might occur. We demonstrate that the two active sites in the dimer exhibit positive cooperativity, with a Hill coefficient of ~1.5. Positive cooperativity has also been observed in the homodimeric mammalian membrane-bound guanylate cyclases. The structure described here provides a reliable model for functional analysis of mammalian guanylate cyclases, which are closely related in sequence.The second messenger 3',5'-cyclic guanosine monophosphate (cGMP) is central to many signal transduction pathways, primarily eliciting effects by modulating the activities of phosphodiesterases, protein kinases, and ion channels [1-3]. In mammals, cGMP is synthesized by two distinct classes of guanylate cyclases, which are either cytoplasmic or membrane-bound [4]. Both classes of guanylate cyclase share a catalytic module that is closely related in sequence to that of mammalian adenylate cyclases. The catalytic domain is a class III nucleotide cyclase domain [5], which is distributed widely from bacteria to humans. The class III nucleotide cyclase domain is often found fused to diverse regulatory domains, but is also found as an isolated protein [6-8]. The mammalian membrane-bound guanylate cyclases, which respond to extracellular peptide binding or to the levels of intracellular Ca2+, function in maintenance of fluid homeostasis, inhibition of myocyte hypertrophy, skeletal development, and visual and ol


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