Structural insights into the mechanism of human soluble guanylate cyclase.

Yunlu Kang,Rui Liu,Lei Chen,Jing-Xiang Wu

doi:10.1038/s41586-019-1584-6

Abstract

Soluble guanylate cyclase (sGC) is the primary sensor of nitric oxide. It has a central role in nitric oxide signalling and has been implicated in many essential physiological processes and disease conditions. The binding of nitric oxide boosts the enzymatic activity of sGC. However, the mechanism by which nitric oxide activates the enzyme is unclear. Here we report the cryo-electron microscopy structures of the human sGCα1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the nitric oxide sensor module and the catalytic module. Binding of nitric oxide to the β1 haem-nitric oxide and oxygen binding (H-NOX) domain triggers the structural rearrangement of the sensor module and a conformational switch of the transducer module from bending to straightening. The resulting movement of the N termini of the catalytic domains drives structural changes within the catalytic module, which in turn boost the enzymatic activity of sGC.

Highlights

Nitric oxide (NO) is a unique gaseous signaling molecule involved in many important physiological processes, such as vasodilatation, neurotransmission, platelet aggregation, immunity, cell proliferation, and mitochondrial respiration (Hollenberg and Cinel, 2009; Horst and Marletta, 2018)
The NO donor nitroglycerin has been widely used for centuries to alleviate angina pectoris, and the soluble guanylate cyclase (sGC) activator riociguat has been approved for the treatment of pulmonary hypertension. sGC activators have therapeutic potential in fibrotic diseases, systemic sclerosis, chronic kidney diseases, neuroprotection, dementia, and sickle cell disease (Sandner, 2018)
We found that sGC composed of human α1 and β1 can be expressed and purified to apparent homogeneity (Figures 1A, S1A and S1B) (Lee et al, 2000). sGC protein composed of an α1 and a β1 subunit is the most predominant isoform, and it has been widely used as a model protein to elucidate the biochemical, biophysical, and structural properties of mammalian sGC (Derbyshire and Marletta, 2012)

Summary

Introduction

Nitric oxide (NO) is a unique gaseous signaling molecule involved in many important physiological processes, such as vasodilatation, neurotransmission, platelet aggregation, immunity, cell proliferation, and mitochondrial respiration (Hollenberg and Cinel, 2009; Horst and Marletta, 2018). NO readily permeates target cell membranes, and after diffusing across the membrane, it binds and activates soluble guanylate cyclase (sGC), the primary NO acceptor. Genetic mutation of sGC in humans is associated with coronary artery disease (Deloukas et al, 2013), moyamoya disease, achalasia, and hypertension (Herve et al, 2014; Wallace et al, 2016), and it is a validated drug target for the treatment of pulmonary hypertension and chronic heart failure. The NO donor nitroglycerin has been widely used for centuries to alleviate angina pectoris, and the sGC activator riociguat has been approved for the treatment of pulmonary hypertension. sGC activators have therapeutic potential in fibrotic diseases, systemic sclerosis, chronic kidney diseases, neuroprotection, dementia, and sickle cell disease (Sandner, 2018)

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Conclusion