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The diatomic gas nitric oxide (NO) serves as an important signaling molecule in mammalian physiology. NO is an effective signaling agent for transient paracrine and autocrine signaling because it freely diffuses through membranes and exhibits a short biological half-life. NO signaling controls diverse circulatory and neural processes, including vasodilation, angiogenesis, neurotransmission, myocardial function, and platelet aggregation. Accordingly, disruptions in NO signaling have been linked to heart disease, stroke, hypertension, and neurodegeneration.


Soluble guanylate cyclase (sGC) is the primary cellular NO receptor. sGC converts GTP to the secondary messenger cGMP. NO produced by the enzyme nitric oxide synthase binds to sGC through a ferrous heme cofactor. Formation of the NO-heme complex initiates a largely uncharacterized conformational change that stimulates cyclase activity several hundred-fold. The burst of cGMP regulates downstream effectors such as phosphodiesterases, ion-gated channels, and cGMP-dependent protein kinases.


sGC is a heterodimeric hemoprotein composed of two homologous subunits, alpha and beta. NO-induced activation presumably occurs via conformational changes communicated from the NO-sensing heme domain to the catalytic domain; however, this regulatory mechanism remains poorly understood. We are interested in addressing the following questions regarding the regulation and function of sGC:


  • How does the binding of NO affect the heme and the local protein environment?

  • How is NO-binding communicated to the catalytic domains?

  • How does a second-site, non-heme NO interaction modulate sGC activity?

  • How do small molecule effectors and therapeutics rescue sGC activity?

  • How do nucleotides regulate sGC activity?

Publications (since 2002):

Horst BG, Yokom AL, Rosenberg DJ, Morris KL, Hammel M, Hurley JH, Marletta MA. Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy. eLife 8:e50634, 2019

Horst BG, Stewart EM, Nazarian AA, Marletta MA. Characterization of a carbon monoxide-activated soluble guanylate cyclase from Chlamydomonas reinhardtii. Biochemistry, 2019

Horst BG and Marletta MA. Physiological activation and deactivation of soluble guanylate cyclase​. Nitric Oxide, 2018, 77, 65–74

Sürmeli NB, Müskens FM, Marletta MA. The influence of nitric oxide on soluble guanylate cyclase regulation by nucleotides: role of the pseudosymmetric site. J Biol Chem 2015, 290:15570-80.


Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J, Kasperaviciute D, Bhosle SG, Mueller M, Geschka S, Rison S, Kojonazarov B, Morrell NW, Neidhardt I, Surmeli NB, Aitman TJ, Stasch JP, Behrends S, Marletta MA. α1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circ Cardiovasc Genet. 2014 7:920-9.


Underbakke ES, Iavarone AT, Chalmers MJ, Pascal BD, Novick S, Griffin PR, Marletta MA. Nitric oxide-induced conformational changes in soluble guanylate cyclase. Structure 2014, 22:512-514.


Campbell MG, Underbakke ES, Potter CS, Carragher B, Marletta MA. Single-particle EM reveals the higher-order domain architecture of soluble guanylate cyclase. Proc Natl Acad Sci USA 2014, 111:2960-2965.


Underbakke ES, Iavarone AT, Marletta MA. Higher-order interactions bridge the nitric oxide receptor and catalytic domains of soluble guanylate cyclase. Proc Natl Acad Sci USA 2013, 110:6777-6782.


Fernhoff NB, Derbyshire ER, Underbakke ES, Marletta MA. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. J Biol Chem 2012, 287:43053-62.


Gunn A, Derbyshire ER, Marletta MA, Britt RD. Conformationally distinct five-coordinate heme-NO complexes of soluble guanylate cyclase elucidated by multifrequency electron paramagnetic resonance (EPR). Biochemistry 2012, 51:8384-90.


Surmeli NB, Marletta MA. Insight into the rescue of soluble guanylate cyclase by the activator cinaciguat. Chembiochem 2012, 13:977-981.


Derbyshire ER, Marletta MA. Structure and Regulation of soluble guanylate cyclase. Annu Rev Biochem 2012, 81:533-59.


Derbyshire ER, Winter MB, Ibrahim M, Deng S, Spiro TG, Marletta MA. Probing domain interactions in soluble guanylate cyclase. Biochemistry 2011, 50:4281-90.


Ibrahim M, Derbyshire ER, Soldatova AV, Marletta MA, Spiro TG. Soluble guanylate cyclase is activated differently by excess NO and by YC-1: resonance raman spectroscopic evidence. Biochemistry 2010, 49:3815-23.


Derbyshire ER, Deng S, Marletta MA. Incorporation of tyrosine and glutamine residues into the soluble guanylate cyclase heme distal pocket alters NO and O2 binding. J Biol Chem 2010, 285:17471-8.


Ibrahim M, Derbyshire ER, Marletta MA, Spiro TG. Probing soluble guanylate cyclase activation by CO and YC-1 using resonance raman spectroscopy. Biochemistry 2010, 49:3815-23.


Fernhoff NB, Derbyshire ER, Marletta MA. A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase. Proc Natl Acad Sci USA 2009, 106:21602-7.


Derbyshire ER, Fernhoff NB, Deng S, Marletta, MA. Nucleotide regulation of soluble guanylate cyclase substrate specificity. Biochemistry 2009, 48:7519-24.


Zimmer M, Gray JM, Pokala N, Chang AJ, Karow DS, Marletta MA, Hudson ML, Morton DB, Chronis N, Bargmann Cl. Neurons detect increases and decreases in oxygen levels using distinct guanylate cyclases. Neuron 2009, 61:865-79.


Derbyshire ER, Marletta MA. Biochemistry of soluble guanylate cyclase. Handb Exp Pharmacol 2009, 191:17-31. Rev.


Derbyshire ER, Gunn A, Ibrahim M, Spiro TG, Britt RD, Marletta MA. Characterization of two different five-coordinate soluble guanylate cyclase ferrous-nitrosyl complexes. Biochemistry 2008, 47:3892-9.


Derbyshire ER, Marletta MA. Butyl isocyanide as a probe of the activation mechanism of soluble guanylate cyclase: investigating the role of non-heme nitric oxide. J Biol Chem 2007, 282:35741-8.


Huang SH, Rio DC, Marletta MA. Ligand binding and inhibition of an oxygen-sensitive soluble guanylate cyclase, Gyc-88E, from Drosophila. Biochemistry 2007, 46:15115-22.


Winger JA, Derbyshire ER, Marletta MA. Dissociation of nitric oxide from soluble guanylate cyclase and heme-nitric oxide/oxygen binding domain constructs. J Biol Chem 2007, 282:897-907.


Hering KW, Artz JD, Pearson WH, Marletta MA. The design and synthesis of YC-1 analogues as probes for soluble guanylate cyclase. Bioorg Med Chem Lett 2006, 16:618-21.


Karow DS, Pan D, Davis JH, Behrends S, Mathies RA, Marletta MA. Characterization of functional heme domains from soluble guanylate cyclase. Biochemistry 2005, 44:16266-74.


Derbyshire ER, Tran R, Mathies RA, Marletta MA. Characterization of nitrosoalkane binding and activation of soluble guanylate cyclase. Biochemistry 2005, 44:16257-65.


Cary SP, Winger JA, Marletta MA. Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by nonheme nitric oxide, ATP, and GTP. Proc Natl Acad Sci USA 2005, 102:13064-9.


Winger JA, Marletta MA. Expression and characterization of the catalytic domains of soluble guanylate cyclase: interaction with the heme domain. Biochemistry 2005, 44:4083-90.


Gray JM, Karow DS, Lu H, Chang AJ, Chang JS, Ellis RE, Marletta MA; Bargmann, CI. Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 2004, 430:317-22.


Ballou DP, Zhao Y, Brandish PE, Marletta MA. Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: the simple NO-binding model is incorrect. Proc Natl Acad Sci USA 2002, 99:12097-101.


Artz JD, Schmidt B, McCracken JL, Marletta MA. Effects of nitroglycerin on soluble guanylate cyclase: implications for nitrate tolerance. J Biol Chem 2002, 277:18253-6.

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