9p2r
Extended, CYR715-bound state of Manduca sexta soluble guanylate cyclase mutant beta C122S
Structural highlights
FunctionPublication Abstract from PubMedSoluble guanylate cyclases (sGCs) are heme-containing, gas-sensing proteins which catalyze the formation of cGMP from GTP. In humans, sGCs are highly selective sensors of nitric oxide (NO) and play a critical role in NO-based regulation of cardiovascular and pulmonary function. The physiological importance of sGC signaling has led to the development of drugs, known as stimulators and activators, which increase sGC catalytic function. Here we characterize a newly developed stimulator, CYR715, which is a particularly potent stimulator of Manduca sexta (Ms) sGC catalytic function even in the absence of NO, increasing activity of the NO-free enzyme to 45% of full catalytic activity. CYR715 also increased the catalytic activity of Ms sGC betaC122A and betaC122S variants, with a marked stimulation of the NO-free betaC122S variant to 74% of maximum. High-resolution cryo-electron microscopy structures were solved for CYR715 bound to Ms sGC betaC122S revealing that CYR715 occupies the same binding site as the characterized sGC stimulators YC-1 and riociguat. Additionally, the core scaffold of CYR715 makes a binding interaction with betaC78 while the flexible tail can interact with alphaR429 or betaY7 and E361. Conformational extension of sGC following NO, YC-1, or CYR715 binding was characterized using small-angle X-ray scattering, revealing that while ligand binding results in sGC extension this extension does not directly correlate to observed activity. This suggests that not all conformational extensions of sGC result in increased catalytic activity, and that effective stimulators assist in converting extension into catalytic function. Molecular Aspects of Soluble Guanylate Cyclase Activation and Stimulator Function.,Houghton KA, Thomas WC, Marletta MA Biochemistry. 2025 Oct 27. doi: 10.1021/acs.biochem.5c00424. PMID:41146038[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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