Nature sub-issue reports the structural mechanism of the activation of nitric oxide receptor sGC by stimulators and activators

On September 17, Chen Lei's research group at the Institute of Molecular Medicine, School of Future Technology, Peking University analyzed the high-resolution structure of the human-derived sGC full-length protein, YC-1 and riociguat, and the activator cinaciguat complex.

Nitric oxide (NO), as a gas signal molecule, plays an important role in many physiological processes, including but not limited to vasodilation, platelet aggregation, nerve signal transmission and respiration

sGC is a heterodimeric protein composed of α and β subunits, each subunit contains 4 domains: H-NOX, PAS, CC and catalytic domain

In the wave of searching for sGC stimulants, the first small molecule discovered was YC-1, which can be called the mother of sGC stimulants.

Figure 1: The structure of the complex of sGC with NO and riociguat or YC-1

Cinaciguat is a typical representative of sGC activators, which can bind and activate heme or sGC without heme

Through further structural comparison and mutant activity detection, the authors found that the combination of cinaciguat in the stretched conformation of sGC promoted the C-terminus of αF resulting in a conformational change of the receptor module, which was transferred to the catalytic module via the transducer module to activate sGC

Figure 2: The structure of sGC and cinaciguat complex

This study revealed the molecular basis for sGC to combine with YC-1 type stimulators and cinaciguat type activators to activate sGC, laying a foundation for further optimization and development of small molecule drugs that activate sGC

Figure 3: Pattern diagram of sGC activation by stimulant and activator

This research was mainly done by Liu Rui, a PhD student at the Institute of Molecular Medicine, Peking University Future Technology College, and a postdoctoral fellow, Kang Yunlu

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2 Poulos, TL Solubleguanylatecyclase.

3 Dasgupta, A.

4 Kang, Y.

5 Olesen, SPetal.

6 Evgenov, OVetal.

7 Follmann, M.