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Article
Nitric Oxide-Induced Conformational Changes in Soluble Guanylate Cyclase
Structure (2014)
  • Eric S. Underbakke, The Scripps Research Institute
  • Anthony T. Iavarone, University of California, Berkeley
  • Michael J. Chalmers, The Scripps Research Institute
  • Bruce D. Pascal, The Scripps Research Institute
  • Scott Novick, The Scripps Research Institute
  • Patrick R. Griffin, The Scripps Research Institute
  • Michael A. Marletta, The Scripps Research Institute
Abstract
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 NObinding
to activation of the catalytic domain.
Publication Date
April 8, 2014
DOI
10.1016/j.str.2014.01.008
Publisher Statement
Copyright 2014 Elsevier Ltd
Citation Information
Eric S. Underbakke, Anthony T. Iavarone, Michael J. Chalmers, Bruce D. Pascal, et al.. "Nitric Oxide-Induced Conformational Changes in Soluble Guanylate Cyclase" Structure Vol. 22 Iss. 4 (2014) p. 602 - 611
Available at: http://works.bepress.com/eric-underbakke/5/