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Molecular steps in sGC activation

In higher animals, soluble guanylate cyclase (sGC) functions as a selective sensor for NO. sGC belongs to a larger family of proteins termed the H-NOX family (H eme N itric oxide/OX ygen binding proteins) that includes prokaryotic counterparts from aerobic and anaerobic organisms [15]. A molecular basis for the ligand discrimination against O2 in NO-regulated sGCs has been proposed [4, 5] and further results support the general aspects of the hypothesis that involve a H-bonding residue in those H-NOXs that bind O2 (Fig. 1).

Figure 1
figure 1

Oxygen binding site in the T. tengcongensis H-NOX domain. Shown on the right are the key residues involved in coordinating the bound O2 including Y140 [4].

This hypothesis has been tested by genome searching and biochemical experiments and indeed, O2-regulated cyclases have been found in C. elegans [6] and other organisms. Most recent results suggest that some bacterial H-NOXs, such as that from Shewanella oneidensis, are serving as NO sensors. In S. oneidensis the NO-bound complex of the H-NOX selectively controls the activity of a cognate histidine kinase. The unligated H-NOX and CO complex have no effect on kinase activity (Fig. 2).

Figure 2
figure 2

Effect of the SO2144 H-NOX on the kinase activity of SO2145. Kinase assays with SO H-NOX analyzed by SDS-PAGE/autoradiography. Top: Autoradiograph. B is a blank lane; C is a control with unligated H-NOX-Fe2+. Bottom: Plot of relative signal intensity. The H-NOX Fe2+-CO (right panel) complex has little effect on kinase activity. Top: Autoradiograph. Bottom: Plot of relative signal intensity.

In addition, further structural studies have delineated the conformational changes that take place upon activation of an NO sensor prokaryotic H-NOX domain. Relevance of these conformational changes to sGC is being investigated. A recnt report bearing on this has appeared [7].

NO binding to the heme remains as a key molecular activation step; however, it has become clear that activation and deactivation are regulated in a complex manner [810]. Evidence suggests regulation by an additional NO binding site and allosteric regulation by ATP and GTP.


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We gratefully acknowledge financial support from the NIH (GM070671), and the Aldo DeBenedictis Fund.

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Correspondence to Michael A Marletta.

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Boon, E.M., Cary, S.P., Huang, S.H. et al. Molecular steps in sGC activation. BMC Pharmacol 7 (Suppl 1), S27 (2007).

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