Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO.
Maps have been deposited to EMDB (20282, 20283) as well the C-alpha traces are deposited to the PDB (6PAS, 6PAT) for the inactive and active states.
- Michael A Marletta
- Benjamin G Horst
- Michal Hammel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Wilfred A van der Donk, University of Illinois at Urbana-Champaign, United States
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