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Molecular aspects of sGC regulation
BMC Pharmacology volume 11, Article number: O10 (2011)
Mammalian sGC is a heterodimer composed of α- and β-subunits (Figure 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.
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.
Derbyshire ER, Marletta MA: Biochemistry of soluble guanylate cyclase. Handb Exp Pharmacol. 2009, 191: 17-31. 10.1007/978-3-540-68964-5_2.
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Marletta, M.A., Underbakke, E.S. & Fernhoff, N.B. Molecular aspects of sGC regulation. BMC Pharmacol 11, O10 (2011). https://doi.org/10.1186/1471-2210-11-S1-O10
- Mass Spectrometry
- Molecular Mechanism
- Sequence Analysis
- Conformational Change
- Catalytic Domain