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J. Biol. Chem., Vol. 283, Issue 27, 18841-18851, July 4, 2008

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An Enzyme-linked Receptor Mechanism for Nitric Oxide-activated Guanylyl Cyclase^*

From the Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, United Kingdom

Nitric oxide (NO) exerts physiological effects by activating specialized receptors that are coupled to guanylyl cyclase activity, resulting in cGMP synthesis from GTP. Despite its widespread importance as a signal transduction pathway, the way it operates is still understood only in descriptive terms. The present work aimed to elucidate a formal mechanism for NO receptor activation and its modulation by GTP, ATP, and allosteric agents, such as YC-1 and BAY 41-2272. The model comprised a module in which NO, the nucleotides, and allosteric agents bind and the protein undergoes a conformational change, dovetailing with a catalytic module where GTP is converted to cGMP and pyrophosphate. Experiments on NO-activated guanylyl cyclase purified from bovine lung allowed values for all of the binding and isomerization constants to be derived. The catalytic module was a modified version of one describing the kinetics of adenylyl cyclase. The resulting enzyme-linked receptor mechanism faithfully reproduces all of the main functional properties of NO-activated guanylyl cyclase reported to date and provides a thermodynamically sound interpretation of those properties. With appropriate modification, it also replicates activation by carbon monoxide and the remarkable enhancement of that activity brought about by the allosteric agents. In addition, the mechanism enhances understanding of the behavior of the receptor in a cellular setting.

Received for publication, March 3, 2008 , and in revised form, May 6, 2008.

^* This work was supported by a program grant from the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7.

¹ Recipient of a Medical Research Council (UK) Research studentship.

² Supported by a bursary from the Jean Shanks Foundation.

³ To whom correspondence should be addressed. Tel.: 44-20-7679-6694; Fax: 44-20-7209-0470; E-mail: john.garthwaite{at}ucl.ac.uk.

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