Volume 11 Supplement 1

5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Molecular aspects of sGC regulation

  • Michael A Marletta1Email author,
  • Eric S Underbakke1 and
  • Nathaniel B Fernhoff1
BMC Pharmacology201111(Suppl 1):O10

https://doi.org/10.1186/1471-2210-11-S1-O10

Published: 1 August 2011

Mammalian sGC is a heterodimer composed of α- and β-subunits (Figure 1) [1]. The C-terminus of each subunit contains a catalytic domain, and the active site is composed of residues from both subunits. Sequence analysis shows that each subunit also contains a well-defined PAS-like domain, and a predicted helical region. The N-termini of the α- and β-subunits are homologous to the H-NOX (H eme-N itric oxide/OX ygen) family of proteins. The N-terminus of β-subunit contains a ferrous heme cofactor that serves a receptor for NO.
Figure 1

Schematic of sGC regulation by NO. In the resting, unliganded state, sGC has a low basal activity. The addition of NO leads initially to a 6-coordinate complex that then forms a highly active 5-coordinate complex. Evidence supports an additional requirement for NO that accelerates the formation of the 5-coordinate complex and fully activates the enzyme.

Ferric heme oxidized sGC has low activity, and the NO complex of the re-reduced heme generates a desensitized, low-activity state of sGC. The molecular mechanism for this desensitization involves site specific S-nitrosation. The conformational changes associated with activation are both subtle and complex. Hydrogen-deuterium exchange mass spectrometry analysis can be used to probe conformational changes and protein-protein interactions. This method has been brought to bear on sGC, illuminating domain interactions within sGC and conformational changes induced by NO binding.

Authors’ Affiliations

(1)
University of California, Berkeley

References

  1. Derbyshire ER, Marletta MA: Biochemistry of soluble guanylate cyclase. Handb Exp Pharmacol. 2009, 191: 17-31. 10.1007/978-3-540-68964-5_2.View ArticlePubMedGoogle Scholar

Copyright

© Marletta et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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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