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Molecular steps in soluble guanylate cyclase activation

Soluble guanylate cyclase (sGC) is a hemoprotein that is selectively activated by specifically binding NO. Once activated sGC synthesizes cyclic GMP from GTP which then triggers reactions essential to animal physiology. sGC essentially functions as a selective sensor for NO. sGC belongs to a recently identified group of proteins termed the H-NOX family (Heme Nitric oxide/OXygen binding proteins) that includes bacterial counterparts from aerobic and anaerobic organisms [14]. Based on our recent structure of a family member [3], a molecular basis for the ligand discrimination against O2 in NO-regulated sGCs has been established. Further studies have pointed towards O2-regulated sGCs in C. elegans [5]. 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 [6, 7]. In the accepted model shown below, NO binds to the sGC heme, activating the enzyme after conversion to the 5-coordinate nitrosyl complex.

Our most recent results show that in the presence of physiological concentrations of ATP and GTP, NO dissociation from the sGC heme is ~500 times slower than the rate of enzyme deactivation in vitro. Deactivated sGC still has NO bound to the heme, and full activation requires additional NO. We propose an activation model shown below where, in the presence of both ATP and GTP, tonic NO forms a stable heme complex with low sGC activity; acute production of NO transiently and fully activates this NO-bound sGC.

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  1. Iyer LM, Anantharaman V, Aravind L: Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins. BMC Genomics. 2003, 6: 5-10.1186/1471-2164-4-5.

    Article  Google Scholar 

  2. Karow DS, Pan D, Pellicena P, Presley A, Mathies RA, Marletta MA: Spectroscopic characterization of the sGC-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis. Biochemistry. 2004, 43: 10203-10211. 10.1021/bi049374l.

    Article  CAS  PubMed  Google Scholar 

  3. Pellicena P, Karow DS, Boon EM, Marletta MA, Kuriyan J: Crystal structure of an oxygen binding H-NOX domain related to soluble guanylate cyclases. Proc Natl Acad Sci U S A. 2004, 101: 12854-12859. 10.1073/pnas.0405188101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Boon EM, Huang SH, Marletta MA: A molecular basis for NO selectivity in soluble guanylate cyclase. Nature Chemical Biology. 2005,

    Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Cary SPL, Winger JA, Marletta MA: Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by non-heme NO, ATP, and GTP. 2005,

    Google Scholar 

  7. Russwurm M, Koesling D: NO activation of guanylyl cyclase. Embo J. 2004, 23: 4443-4450. 10.1038/sj.emboj.7600422.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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We gratefully acknowledge financial support from the Aldo DeBenedictis Fund, LDRD fund from the Lawrence Berkeley National Laboratory and the National Institutes of Health.

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Correspondence to Michael A Marletta.

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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 ( ), 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 soluble guanylate cyclase activation . BMC Pharmacol 5 (Suppl 1), S1 (2005).

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