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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.

Kumar V, Martin F, Hahn MG, Schaefer M, Stamler JS, Stasch JP, van den Akker F
Biochemistry 52 3601-8 (2013)
Related entries: 4iah, 4iam

Cited: 36 times
EuropePMC logo PMID: 23614626

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.

Articles - 4iae mentioned but not cited (4)

  1. 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. Kumar V, Martin F, Hahn MG, Schaefer M, Stamler JS, Stasch JP, van den Akker F. Biochemistry 52 3601-3608 (2013)
  2. Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains. Rehan Khalid R, Tahir Ul Qamar M, Maryam A, Ashique A, Anwar F, H Geesi M, Siddiqi AR. Molecules 23 E2141 (2018)
  3. Regulation of Neuronal Oxygen Responses in C. elegans Is Mediated through Interactions between Globin 5 and the H-NOX Domains of Soluble Guanylate Cyclases. Abergel Z, Chatterjee AK, Zuckerman B, Gross E. J Neurosci 36 963-978 (2016)
  4. Replacement of heme by soluble guanylate cyclase (sGC) activators abolishes heme-nitric oxide/oxygen (H-NOX) domain structural plasticity. Argyriou AI, Makrynitsa GI, Dalkas G, Georgopoulou DA, Salagiannis K, Vazoura V, Papapetropoulos A, Topouzis S, Spyroulias GA. Curr Res Struct Biol 3 324-336 (2021)


Reviews citing this publication (16)

  1. Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator. Vanhoutte PM, Zhao Y, Xu A, Leung SW. Circ Res 119 375-396 (2016)
  2. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Follmann M, Griebenow N, Hahn MG, Hartung I, Mais FJ, Mittendorf J, Schäfer M, Schirok H, Stasch JP, Stoll F, Straub A. Angew Chem Int Ed Engl 52 9442-9462 (2013)
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  4. Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor. Beuve A. Antioxid Redox Signal 26 137-149 (2017)
  5. Computational Structural Biology of S-nitrosylation of Cancer Targets. Bignon E, Allega MF, Lucchetta M, Tiberti M, Papaleo E. Front Oncol 8 272 (2018)
  6. Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow. Rogers NM, Seeger F, Garcin ED, Roberts DD, Isenberg JS. Front Physiol 5 134 (2014)
  7. New insights into the role of soluble guanylate cyclase in blood pressure regulation. Buys E, Sips P. Curr Opin Nephrol Hypertens 23 135-142 (2014)
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  9. Structures of soluble guanylate cyclase: implications for regulatory mechanisms and drug development. Gileadi O. Biochem Soc Trans 42 108-113 (2014)
  10. Stimulators and activators of soluble guanylate cyclase for urogenital disorders. Mónica FZ, Antunes E. Nat Rev Urol 15 42-54 (2018)
  11. Iron transitions during activation of allosteric heme proteins in cell signaling. Négrerie M. Metallomics 11 868-893 (2019)
  12. Bacterial Haemoprotein Sensors of NO: H-NOX and NosP. Bacon B, Nisbett LM, Boon E. Adv Microb Physiol 70 1-36 (2017)
  13. Drug discovery targeting heme-based sensors and their coupled activities. Sousa EH, Lopes LG, Gonzalez G, Gilles-Gonzalez MA. J Inorg Biochem 167 12-20 (2017)
  14. Redox Switches Controlling Nitric Oxide Signaling in the Resistance Vasculature and Implications for Blood Pressure Regulation: Mid-Career Award for Research Excellence 2020. Aramide Modupe Dosunmu-Ogunbi A, Galley JC, Yuan S, Schmidt HM, Wood KC, Straub AC. Hypertension 78 912-926 (2021)
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  16. The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management. Maiuolo J, Oppedisano F, Carresi C, Gliozzi M, Musolino V, Macrì R, Scarano F, Coppoletta A, Cardamone A, Bosco F, Mollace R, Muscoli C, Palma E, Mollace V. Int J Mol Sci 23 15454 (2022)

Articles citing this publication (16)

  1. Nitric oxide and heat shock protein 90 activate soluble guanylate cyclase by driving rapid change in its subunit interactions and heme content. Ghosh A, Stasch JP, Papapetropoulos A, Stuehr DJ. J Biol Chem 289 15259-15271 (2014)
  2. S-Nitrosation of Conserved Cysteines Modulates Activity and Stability of S-Nitrosoglutathione Reductase (GSNOR). Guerra D, Ballard K, Truebridge I, Vierling E. Biochemistry 55 2452-2464 (2016)
  3. Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Ghosh A, Koziol-White CJ, Asosingh K, Cheng G, Ruple L, Groneberg D, Friebe A, Comhair SA, Stasch JP, Panettieri RA, Aronica MA, Erzurum SC, Stuehr DJ. Proc Natl Acad Sci U S A 113 E2355-62 (2016)
  4. A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection. Langhauser F, Casas AI, Dao VT, Guney E, Menche J, Geuss E, Kleikers PWM, López MG, Barabási AL, Kleinschnitz C, Schmidt HHHW. NPJ Syst Biol Appl 4 8 (2018)
  5. Soluble guanylyl cyclase (sGC) degradation and impairment of nitric oxide-mediated responses in urethra from obese mice: reversal by the sGC activator BAY 60-2770. Alexandre EC, Leiria LO, Silva FH, Mendes-Silvério CB, Calmasini FB, Davel AP, Mónica FZ, De Nucci G, Antunes E. J Pharmacol Exp Ther 349 2-9 (2014)
  6. Guanylyl cyclase sensitivity to nitric oxide is protected by a thiol oxidation-driven interaction with thioredoxin-1. Huang C, Alapa M, Shu P, Nagarajan N, Wu C, Sadoshima J, Kholodovych V, Li H, Beuve A. J Biol Chem 292 14362-14370 (2017)
  7. Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. Ghosh A, Stuehr DJ. Antioxid Redox Signal 26 182-190 (2017)
  8. Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60-2770 in rabbit corpus cavernosum. Estancial CS, Rodrigues RL, De Nucci G, Antunes E, Mónica FZ. BJU Int 116 657-664 (2015)
  9. Structure/activity relationships of (M)ANT- and TNP-nucleotides for inhibition of rat soluble guanylyl cyclase α1β1. Dove S, Danker KY, Stasch JP, Kaever V, Seifert R. Mol Pharmacol 85 598-607 (2014)
  10. The soluble guanylyl cyclase activator BAY 60-2770 inhibits murine allergic airways inflammation and human eosinophil chemotaxis. Baldissera L, Squebola-Cola DM, Calixto MC, Lima-Barbosa AP, Rennó AL, Anhê GF, Condino-Neto A, De Nucci G, Antunes E. Pulm Pharmacol Ther 41 86-95 (2016)
  11. Hypoxia inhibits adenylyl cyclase catalytic activity in a porcine model of persistent pulmonary hypertension of the newborn. Sikarwar AS, Hinton M, Santhosh KT, Dhanaraj P, Talabis M, Chelikani P, Dakshinamurti S. Am J Physiol Lung Cell Mol Physiol 315 L933-L944 (2018)
  12. (1)H, (13)C, (15)N backbone and side-chain resonance assignment of Nostoc sp. C139A variant of the heme-nitric oxide/oxygen binding (H-NOX) domain. Alexandropoulos II, Argyriou AI, Marousis KD, Topouzis S, Papapetropoulos A, Spyroulias GA. Biomol NMR Assign 10 395-400 (2016)
  13. Mapping of the sGC Stimulator BAY 41-2272 Binding Site on H-NOX Domain and Its Regulation by the Redox State of the Heme. Makrynitsa GI, Argyriou AI, Zompra AA, Salagiannis K, Vazoura V, Papapetropoulos A, Topouzis S, Spyroulias GA. Front Cell Dev Biol 10 925457 (2022)
  14. 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. Dai Y, Stuehr DJ. Mol Pharmacol 103 286-296 (2023)
  15. Direct Measurement of S-Nitrosothiols with an Orbitrap Fusion Mass Spectrometer: S-Nitrosoglutathione Reductase as a Model Protein. Guerra D, Truebridge I, Eyles SJ, Treffon P, Vierling E. Methods Mol Biol 1747 143-160 (2018)
  16. The H-NOX protein structure adapts to different mechanisms in sensors interacting with nitric oxide. Yoo BK, Kruglik SG, Lambry JC, Lamarre I, Raman CS, Nioche P, Negrerie M. Chem Sci 14 8408-8420 (2023)


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