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Guanylyl cyclase, α1β1

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Target not currently curated in GtoImmuPdb

Target id: 1287

Nomenclature: Guanylyl cyclase, α1β1

Abbreviated Name: GC-1

Family: Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase

Contents:

Quaternary Structure: Subunits
Guanylyl cyclase α1 subunit
Guanylyl cyclase β1 subunit
Quaternary Structure Comments
Cryo-EM structural analysis of GC-1 has revealed the mechanism by which NO activates the enzyme [6-7].
Previous and Unofficial Names Click here for help
NOGCR α1β1 | sGC | Soluble guanylyl cyclase
Database Links Click here for help
BRENDA 4.6.1.2
KEGG Enzyme 4.6.1.2
Enzyme Reaction Click here for help
EC Number: 4.6.1.2
Endogenous ligand(s)
NO

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Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
praliciguat Small molecule or natural product Immunopharmacology Ligand Hs Activation 6.6 pEC50 16
⤷ pEC50 6.6 (EC50 2.67x10-7 M) [16]
Description: Concentration-dependent increase in the production of cGMP
BAY 41-8543 Small molecule or natural product Rn Activation 8.0 pIC50 10
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [10]
Description: Determined as inhibition of phenylepherine-induced vasoconstriction in rat thoracic aorta rings
NO Approved drug Primary target of this compound Click here for species-specific activity table Hs Activation - -
⤷
ataciguat Small molecule or natural product Hs Activation - - 12
⤷ [12]
BAY412272 Small molecule or natural product Ligand has a PDB structure Hs Activation - - 13
⤷ [13]
cinaciguat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Activation - - 15
⤷ [Binds to: apo-GC-1] [15]
riociguat Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Activation - - 13-14
⤷ [13-14]
YC-1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Activation - - 3,8,11
⤷ [3,8,11]
vericiguat Small molecule or natural product Approved drug Click here for species-specific activity table Hs Activation - - 2
⤷ [2]
olinciguat Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Activation - - 1
⤷ [1]
runcaciguat Small molecule or natural product Ligand has a PDB structure Hs Activation - - 5
⤷ [5]
Activator Comments
Like latanoprostene bunod, nitroglycerin, isosorbide mononitrate and isosorbide dinitrate are NO donors.
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
NS 2028 Small molecule or natural product Ligand has a PDB structure Bt Inhibition 8.1 pIC50 9
⤷ pIC50 8.1 [9]
ODQ Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 4
⤷ pIC50 7.5 (IC50 3.16x10-8 M) [4]
View species-specific inhibitor tables
Gene Expression and Pathophysiology Comments
Genetic alterations in the NO-cGMP pathway are associated with risk of developing cardiovascular disease [17].

References

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1. Buys ES, Zimmer DP, Chickering J, Graul R, Chien YT, Profy A, Hadcock JR, Masferrer JL, Milne GT. (2018) Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide, 78: 72-80. [PMID:29859918]

2. Follmann M, Ackerstaff J, Redlich G, Wunder F, Lang D, Kern A, Fey P, Griebenow N, Kroh W, Becker-Pelster EM et al.. (2017) Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem, 60 (12): 5146-5161. [PMID:28557445]

3. Friebe A, Schultz G, Koesling D. (1996) Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. EMBO J, 15 (24): 6863-8. [PMID:9003762]

4. Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B. (1995) Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Mol Pharmacol, 48 (2): 184-8. [PMID:7544433]

5. Hahn MG, Lampe T, El Sheikh S, Griebenow N, Woltering E, Schlemmer KH, Dietz L, Gerisch M, Wunder F, Becker-Pelster EM et al.. (2021) Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042). J Med Chem, 64 (9): 5323-5344. [PMID:33872507]

6. Horst BG, Yokom AL, Rosenberg DJ, Morris KL, Hammel M, Hurley JH, Marletta MA. (2019) Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy. Elife, 8. [PMID:31566566]

7. Kang Y, Liu R, Wu JX, Chen L. (2019) Structural insights into the mechanism of human soluble guanylate cyclase. Nature, 574 (7777): 206-210. [PMID:31514202]

8. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood, 84 (12): 4226-33. [PMID:7527671]

9. Olesen SP, Drejer J, Axelsson O, Moldt P, Bang L, Nielsen-Kudsk JE, Busse R, Mülsch A. (1998) Characterization of NS 2028 as a specific inhibitor of soluble guanylyl cyclase. Br J Pharmacol, 123 (2): 299-309. [PMID:9489619]

10. Roberts LR, Bradley PA, Bunnage ME, England KS, Fairman D, Fobian YM, Fox DN, Gymer GE, Heasley SE, Molette J et al.. (2011) Acidic triazoles as soluble guanylate cyclase stimulators. Bioorg Med Chem Lett, 21 (21): 6515-8. [PMID:21924901]

11. Russwurm M, Behrends S, Harteneck C, Koesling D. (1998) Functional properties of a naturally occurring isoform of soluble guanylyl cyclase. Biochem J, 335 ( Pt 1): 125-30. [PMID:9742221]

12. Schindler U, Strobel H, Schönafinger K, Linz W, Löhn M, Martorana PA, Rütten H, Schindler PW, Busch AE, Sohn M et al.. (2006) Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase. Mol Pharmacol, 69 (4): 1260-8. [PMID:16332991]

13. Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U et al.. (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature, 410 (6825): 212-5. [PMID:11242081]

14. Stasch JP, Hobbs AJ. (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol, (191): 277-308. [PMID:19089334]

15. Stasch JP, Schmidt P, Alonso-Alija C, Apeler H, Dembowsky K, Haerter M, Heil M, Minuth T, Perzborn E, Pleiss U et al.. (2002) NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol, 136 (5): 773-83. [PMID:12086987]

16. Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S et al.. (2018) Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease. J Pharmacol Exp Ther, 365 (3): 664-675. [PMID:29643251]

17. Wobst J, Schunkert H, Kessler T. (2018) Genetic alterations in the NO-cGMP pathway and cardiovascular risk. Nitric Oxide, 76: 105-112. [PMID:29601927]

Contributors

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