NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism
NO and CO differentially activate soluble guanylyl cyclase via a heme pivot-bend mechanism
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DOI：
10.1038/sj.emboj.7601521
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发表时间：
2007-01-24
期刊：
影响因子：
11.4
通讯作者：
van den Akker, Focco
中科院分区：
文献类型：
--
作者：
Ma, Xiaolei;Sayed, Nazish;van den Akker, Focco
可溶性鸟苷酸环化酶 (sGC) 的双原子配体辨别对于心血管稳态和神经元信号传导至关重要。一氧化氮 (NO) 刺激 sGC 活性达 200 倍，而一氧化碳 (CO) 仅刺激 4 倍。配体辨别以及对 NO 和 CO 的差异反应的分子细节尚不清楚。这些配体由 sGC 的血红素结构域感知，该结构域属于血红素一氧化氮氧 (H-NOX) 结构域家族，在原核生物中也是进化保守的。在这里，我们报告了蓝藻同系物的游离、NO 结合和 CO 结合 H-NOX 结构域的晶体结构。 sGC 中的这些结构和互补突变分析揭示了一种分子统治者机制，该机制允许 sGC 在排除氧的同时更青睐 NO 而不是 CO，同时利用差异血红素枢转和血红素弯曲的信号传导。因此，血红素充当弯曲楔子，允许 H-NOX 的 N 端子结构域在 sGC 激活时与六到五配位的 NO 结合状态的转变同时发生变化。这种转变可以通过 sGC 残基 74 和 145 以及蓝藻 H-NOX 同系物中相应残基的突变来调节。
Diatomic ligand discrimination by soluble guanylyl cyclase (sGC) is paramount to cardiovascular homeostasis and neuronal signaling. Nitric oxide (NO) stimulates sGC activity 200-fold compared with only four-fold by carbon monoxide (CO). The molecular details of ligand discrimination and differential response to NO and CO are not well understood. These ligands are sensed by the heme domain of sGC, which belongs to the heme nitric oxide oxygen (H-NOX) domain family, also evolutionarily conserved in prokaryotes. Here we report crystal structures of the free, NO-bound, and CO-bound H-NOX domains of a cyanobacterial homolog. These structures and complementary mutational analysis in sGC reveal a molecular ruler mechanism that allows sGC to favor NO over CO while excluding oxygen, concomitant to signaling that exploits differential heme pivoting and heme bending. The heme thereby serves as a flexing wedge, allowing the N-terminal subdomain of H-NOX to shift concurrent with the transition of the six-to five-coordinated NO-bound state upon sGC activation. This transition can be modulated by mutations at sGC residues 74 and 145 and corresponding residues in the cyanobacterial H-NOX homolog.