ArticleBiochemistry2013
Insights into BAY 60-2770 activation and S-nitrosylation-dependent desensitization of soluble guanylyl cyclase via crystal structures of homologous nostoc H-NOX domain complexes.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 58 citations in OpenAlex.
- NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma.Redox biology · 2026Article
- Oxidative Activation of the Heme Nitric Oxide/Oxygen-Binding Protein (H-NOX) fromBiochemistry · 2025Article
- Protein S-Nitrosylation: A Chemical Modification with Ubiquitous Biological Activities.The protein journal · 2024Review
- Promising Cerebral Blood Flow Enhancers in Acute Ischemic Stroke.Translational stroke research · 2023Review
- The H-NOX protein structure adapts to different mechanisms in sensors interacting with nitric oxide.Chemical science · 2023Article
- BAY58-2667 Activates Different Soluble Guanylyl Cyclase Species by Distinct Mechanisms that Indicate Its Principal Target in Cells is the Heme-Free Soluble Guanylyl Cyclase-Heat Shock Protein 90 Complex.Molecular pharmacology · 2023Article
- The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management.International journal of molecular sciences · 2022Review
- Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme.Frontiers in cell and developmental biology · 2022Article
- Redox Switches Controlling Nitric Oxide Signaling in the Resistance Vasculature and Implications for Blood Pressure Regulation: Mid-Career Award for Research Excellence 2020.Hypertension (Dallas, Tex. : 1979) · 2021Review
- Replacement of heme by soluble guanylate cyclase (sGC) activators abolishes heme-nitric oxide/oxygen (H-NOX) domain structural plasticity.Current research in structural biology · 2021Article
- Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains.Molecules (Basel, Switzerland) · 2018Article
- Computational Structural Biology ofFrontiers in oncology · 2018Review
- Stimulators and activators of soluble guanylate cyclase for urogenital disorders.Nature reviews. Urology · 2018Review
- A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection.NPJ systems biology and applications · 2018Article
- Direct Measurement of S-Nitrosothiols with an Orbitrap Fusion Mass Spectrometer: S-Nitrosoglutathione Reductase as a Model Protein.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Guanylyl cyclase sensitivity to nitric oxide is protected by a thiol oxidation-driven interaction with thioredoxin-1.The Journal of biological chemistry · 2017Article
- Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives.Antioxidants & redox signaling · 2017Article
- Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor.Antioxidants & redox signaling · 2017Review
- Bacterial Haemoprotein Sensors of NO: H-NOX and NosP.Advances in microbial physiology · 2017Review
- S-Nitrosation of Conserved Cysteines Modulates Activity and Stability of S-Nitrosoglutathione Reductase (GSNOR).Biochemistry · 2016Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The soluble guanylyl cyclase (sGC) is an important receptor for nitric oxide (NO). Nitric oxide activates sGC several hundred fold to generate cGMP from GTP. Because of sGC's salutary roles in cardiovascular physiology, it has received substantial attention as a drug target. The heme domain of sGC is key to its regulation as it not only contains the NO activation site but also harbors sites for NO-independent sGC activators as well an S-nitrosylation site (β1 C122) involved in desensitization. Here we report the crystal structure of the activator BAY 60-2770 bound to the Nostoc H-NOX domain that is homologous to sGC. The structure reveals that BAY 60-2770 has displaced the heme and acts as a heme mimetic via carboxylate-mediated interactions with the conserved YxSxR motif as well as hydrophobic interactions. Comparisons with the previously determined BAY 58-2667 bound structure reveal that BAY 60-2770 is more ordered in its hydrophobic tail region. sGC activity assays demonstrate that BAY 60-2770 has about 10% higher fold maximal stimulation compared to BAY 58-2667. S-Nitrosylation of the BAY 60-2770 substituted Nostoc H-NOX domain causes subtle changes in the vicinity of the S-nitrosylated C122 residue. These shifts could impact the adjacent YxSxR motif and αF helix and as such potentially inhibit either heme incorporation or NO-activation of sGC and thus provide a structural basis for desensitization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.