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  • Oral presentation
  • Open Access

Molecular steps in sGC activation

  • 1,
  • 1,
  • 2,
  • 1,
  • 2,
  • 2,
  • 1 and
  • 1, 2, 3Email author
BMC Pharmacology20077 (Suppl 1) :S27

  • Published:


  • Histidine
  • Conformational Change
  • Guanylate Cyclase
  • Activation Step
  • Histidine Kinase
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.



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

Authors’ Affiliations

Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA


  1. Iyer LM, Anantharaman V, Aravind L: Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins. BMC Genomics. 2003, 4: 5-10.1186/1471-2164-4-5.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Karow DS, Pan D, Tran R, Pellicena P, Presley A, Mathies RA, Marletta MA: Spectroscopic characterization of the soluble guanylate cyclase-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis. Biochemistry. 2004, 43: 10203-10211. 10.1021/bi049374l.View ArticlePubMedGoogle Scholar
  3. Nioche P, Berka V, Vipond J, Minton N, Tsai AL, Raman CS: Femtomolar sensitivity of a NO sensor from Clostridium botulinum. Science. 2004, 306: 1550-1553. 10.1126/science.1103596.View ArticlePubMedGoogle Scholar
  4. Pellicena P, Karow DS, Boon EM, Marletta MA, Kuriyan J: Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases. Proc Natl Acad Sci. 2004, 101: 12854-12859. 10.1073/pnas.0405188101.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Boon EM, Huang SH, Marletta MA: A molecular basis for NO selectivity in soluble guanylate cyclase. Nat Chem Biol. 2005, 1: 53-59. 10.1038/nchembio704.View ArticlePubMedGoogle Scholar
  6. Gray JM, Karow DS, Lu H, Chang AJ, Chang JS, Ellis RE, Marletta MA, Bargmann CI: Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature. 2004, 430: 317-322. 10.1038/nature02714.View ArticlePubMedGoogle Scholar
  7. Ma X, Sayed N, Beuve A, van den Akker F: NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism. EMBO J. 2007, 26: 578-588. 10.1038/sj.emboj.7601521.PubMed CentralView ArticlePubMedGoogle Scholar
  8. Russwurm M, Koesling D: NO activation of guanylyl cyclase. EMBO J. 2004, 23: 4443-4450. 10.1038/sj.emboj.7600422.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Cary SP, Winger JA, Derbyshire ER, Marletta MA: Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci. 2006, 31: 231-239. 10.1016/j.tibs.2006.02.003.View ArticlePubMedGoogle Scholar
  10. Cary SP, Winger JA, Marletta MA: Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by nonheme nitric oxide, ATP, and GTP. Proc Natl Acad Sci. 2005, 102: 13064-13069. 10.1073/pnas.0506289102.PubMed CentralView ArticlePubMedGoogle Scholar


© Boon et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.