Conformational changes involved in sGC activation
© Marletta et al; licensee BioMed Central Ltd. 2013
Published: 29 August 2013
Soluble guanylate cyclase (sGC) is a central target of nitric oxide (NO) action. sGC is a heterodimeric hemoprotein. The ferrous heme efficiently traps NO and plays an intimate role in activation of the enzyme to catalyse the conversion of GTP to cGMP. sGC is also the target for cardiovascular therapies involving small molecules that stimulate sGC directly or activate oxidized or apo sGC. Efforts to fully characterize sGC catalysis have been hampered by the lack of structural information. High-resolution structures of sGC fragments (domains) have been determined and have provided important detail; however, a structure of the full-length protein, an essential piece of the puzzle, remains unsolved.
Together these approaches define the architecture of the sGC holoenzyme, revealing inter-domain interactions responsible for communicating NO-occupancy from the heme to the catalytic site. The resultant structural model of sGC provides insight into the mechanisms of activation of both NO and small molecule modulators.
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