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Molecular steps in sGC activation
BMC Pharmacology volume 7, Article number: S27 (2007)
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 [1–5]. 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).
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).
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 [8–10]. Evidence suggests regulation by an additional NO binding site and allosteric regulation by ATP and GTP.
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Acknowledgements
We gratefully acknowledge financial support from the NIH (GM070671), and the Aldo DeBenedictis Fund.
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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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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). https://doi.org/10.1186/1471-2210-7-S1-S27
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DOI: https://doi.org/10.1186/1471-2210-7-S1-S27