Backbone and side chain NMR assignments of the H-NOX domain from Nostoc sp. in complex with BAY58-2667 (cinaciguat)
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ARTICLE
Backbone and side chain NMR assignments of the H‑NOX domain from Nostoc sp. in complex with BAY58‑2667 (cinaciguat) Garyfallia I. Makrynitsa1 · Aikaterini I. Argyriou1 · Georgios Dalkas1 · Dimitra A. Georgopoulou1 · Marina Bantzi2,3 · Athanassios Giannis2 · Andreas Papapetropoulos4 · Georgios A. Spyroulias1 Received: 21 July 2020 / Accepted: 24 October 2020 © Springer Nature B.V. 2020
Abstract Soluble guanylate cyclase (sGC) enzyme is activated by the gaseous signaling agent nitric oxide (NO) and triggers the conversion of GTP (guanosine 5′-triphosphate) to cGMP (cyclic guanylyl monophosphate). It contains the heme binding H-NOX (heme-nitric oxide/oxygen binding) domain which serves as the sensor of NO and it is highly conserved across eukaryotes and bacteria as well. Many research studies focus on the synthesis of chemical compounds bearing possible therapeutic action, which mimic the heme moiety and activate the sGC enzyme. In this study, we report a preliminary solution NMR (Nuclear Magnetic Resonance) study of the H-NOX domain from Nostoc sp. cyanobacterium in complex with the chemical sGC activator cinaciguat (BAY58-2667). An almost complete sequence-specific assignment of its 1H, 15N and 13C resonances was obtained and its secondary structure predicted by TALOS+. Keywords H-NOX domain · Soluble guanylate cyclase (sGC) · NMR spectroscopy · Cinaciguat · BAY58-2667
Biological context Soluble guanylate cyclase (sGC) is considered as a very attractive therapeutic target for cardiovascular diseases due to its implication to the NO/cGMP signaling pathway (Erdmann et al. 2013). Nitric oxide (NO) acts as a key regulatory molecule of the sGC enzyme, upon binding on the N-terminal H-NOX (heme-nitric oxide/oxygen binding) domain. This event leads to the activation of sGC and subsequently to the conversion of GTP (guanosine 5′-triphosphate) to cGMP (cyclic guanylyl monophosphate) (Ma et al. Garyfallia I. Makrynitsa and Aikaterini I. Argyriou have equally contributed to this work. * Georgios A. Spyroulias [email protected] 1
Department of Pharmacy, University of Patras, 26504 Patras, Greece
2
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
3
Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland
4
Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
2007; Underbakke et al. 2014). Loss of the heme cofactor of H-NOX domain and low levels of NO bioavailability are responsible for the malfunction of the NO/cGMP pathway resulting to heart disease, neurodegeneration, hypertension and erectile dysfunction as well (Breitenstein et al. 2016; Friebe et al. 2007; Gheorghiade et al. 2013). Two classes of chemical compounds have characterized to act towards sGC in a NO-independent manner, stimulators and activators. Stimulators are heme-dependent compounds while activators act on a heme free or heme-oxidized sGC (Follmann et al. 2013; Nossaman et al. 2012)
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