Nitric oxide-induced conformational changes in soluble guanylate cyclase.

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Signaling

Background:

• Soluble guanylate cyclase (sGC) mediates nitric oxide (NO) signaling.
• NO activates sGC by binding its heme cofactor, stimulating cyclic-GMP (cGMP) synthesis.
• sGC is crucial for physiological processes like vasodilation and neurotransmission, but NO-induced activation mechanisms are unclear.

Purpose of the Study:

• To investigate the NO-induced conformational changes in sGC.
• To elucidate the allosteric pathway linking NO binding to sGC catalytic activation.

Main Methods:

• Hydrogen/deuterium exchange mass spectrometry (HDX-MS) was used to probe sGC structure.
• HDX-MS analyzed conformational changes upon NO binding to sGC.

Main Results:

• HDX-MS identified NO-induced conformational changes in discrete sGC regions.
• NO binding to the H-NOX domain affected PAS domain interactions.
• Conformational changes propagated from the PAS-helical junction to the catalytic domain, contracting the active site pocket.

Conclusions:

• NO binding to sGC induces a series of allosteric conformational changes.
• These changes establish a pathway from NO binding to catalytic domain activation.
• The findings clarify the molecular mechanisms of NO-mediated sGC activation.