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Structure. 2014 Apr 8;22(4):602-11. doi: 10.1016/j.str.2014.01.008. Epub 2014 Feb 20.

Nitric oxide-induced conformational changes in soluble guanylate cyclase.

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Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Chemistry and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:


Soluble guanylate cyclase (sGC) is the primary mediator of nitric oxide (NO) signaling. NO binds the sGC heme cofactor stimulating synthesis of the second messenger cyclic-GMP (cGMP). As the central hub of NO/cGMP signaling pathways, sGC is important in diverse physiological processes such as vasodilation and neurotransmission. Nevertheless, the mechanisms underlying NO-induced cyclase activation in sGC remain unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was employed to probe the NO-induced conformational changes of sGC. HDX-MS revealed NO-induced effects in several discrete regions. NO binding to the heme-NO/O2-binding (H-NOX) domain perturbs a signaling surface implicated in Per/Arnt/Sim (PAS) domain interactions. Furthermore, NO elicits striking conformational changes in the junction between the PAS and helical domains that propagate as perturbations throughout the adjoining helices. Ultimately, NO binding stimulates the catalytic domain by contracting the active site pocket. Together, these conformational changes delineate an allosteric pathway linking NO binding to activation of the catalytic domain.

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