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Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):2960-5. doi: 10.1073/pnas.1400711111. Epub 2014 Feb 10.

Single-particle EM reveals the higher-order domain architecture of soluble guanylate cyclase.

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Department of Integrative Structural and Computational Biology, National Resource for Automated Molecular Microscopy, and Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037.


Soluble guanylate cyclase (sGC) is the primary nitric oxide (NO) receptor in mammals and a central component of the NO-signaling pathway. The NO-signaling pathways mediate diverse physiological processes, including vasodilation, neurotransmission, and myocardial functions. sGC is a heterodimer assembled from two homologous subunits, each comprised of four domains. Although crystal structures of isolated domains have been reported, no structure is available for full-length sGC. We used single-particle electron microscopy to obtain the structure of the complete sGC heterodimer and determine its higher-order domain architecture. Overall, the protein is formed of two rigid modules: the catalytic dimer and the clustered Per/Art/Sim and heme-NO/O2-binding domains, connected by a parallel coiled coil at two hinge points. The quaternary assembly demonstrates a very high degree of flexibility. We captured hundreds of individual conformational snapshots of free sGC, NO-bound sGC, and guanosine-5'-[(α,β)-methylene]triphosphate-bound sGC. The molecular architecture and pronounced flexibility observed provides a significant step forward in understanding the mechanism of NO signaling.

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