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A molecular basis for NO selectivity in soluble guanylate cyclase

Nature Chemical Biology volume 1, pages 53–59 (2005)Cite this article

Abstract

Soluble guanylate cyclases (sGCs) function as heme sensors that selectively bind nitric oxide (NO), triggering reactions essential to animal physiology. Recent discoveries place sGCs in the H-NOX family (heme nitric oxide/oxygen-binding domain), which includes bacterial proteins from aerobic and anaerobic organisms. Some H-NOX proteins tightly bind oxygen (O2), whereas others show no measurable affinity for O2, providing the basis for selective NO signaling in aerobic cells. Using a series of wild-type and mutant H-NOXs, we established a molecular basis for ligand discrimination. A distal pocket tyrosine is requisite for O2 binding in the H-NOX family. These data suggest that sGC uses a kinetic selection against O2; we propose that the O2 dissociation rate in the absence of this tyrosine is fast and that a stable O2 complex does not form.

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Figure 1: Residues important for ligand discrimination in the H-NOX family.
Figure 2: UV-visible spectroscopy of H-NOX proteins after anaerobic reduction (FeII unligated complexes, blue) before and after being exposed to air (FeII–O2 complexes, red).
Figure 3: O2-binding kinetics of Tt H-NOX.

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Acknowledgements

The Laboratory Directed Research and Development (LDRD) Fund from Lawrence Berkeley National Lab provided funding to M.A.M., the US National Science Foundation to S.H.H. and the Ruth L. Kirschstein National Research Service Award to E.M.B. (F32GM069302). We very gratefully acknowledge W. Belliston-Bittner, B. Leigh, J. Winkler and H. Gray at the Beckman Institute Laser Resource Center at the California Institute of Technology for their essential help in measuring oxygen association rates. We also thank J.H. Davis, P. Pellicena and J. Kuriyan at the University of California, Berkeley, as well as J. Dixon at the University of California, San Diego, and D. Ballou at the University of Michigan for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    Elizabeth M Boon & Michael A Marletta

  2. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Shirley H Huang & Michael A Marletta

  3. Division of Physical Biosciences, Lawrence Berkeley National Lab, Berkeley, 94720, California, USA

    Michael A Marletta

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Correspondence to Michael A Marletta.

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Boon, E., Huang, S. & Marletta, M. A molecular basis for NO selectivity in soluble guanylate cyclase. Nat Chem Biol 1, 53–59 (2005). https://doi.org/10.1038/nchembio704

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