Structure of Cinaciguat (BAY 58-2667) Bound to Nostoc H-NOX Domain Reveals Insights into Heme-mimetic Activation of the Soluble Guanylyl Cyclase
Structure of Cinaciguat (BAY 58-2667) Bound to Nostoc H-NOX Domain Reveals Insights into Heme-mimetic Activation of the Soluble Guanylyl Cyclase
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DOI：
10.1074/jbc.m110.111559
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
van den Akker, Focco
中科院分区：
文献类型：
--
作者：
Martin, Faye;Baskaran, Padmamalini;van den Akker, Focco
血红素是所有生命形式的重要分子，血红素能够协助催化、结合配体和进行氧化还原变化。血红素相关功能障碍可导致心血管疾病，其中一些心血管疾病与可溶性鸟苷酸环化酶 (sGC) 的血红素氧化密切相关。 sGC 是主要的一氧化氮 (NO) 受体，可刺激第二信使 cGMP 的产生，而已知活性氧可清除 NO 并氧化/灭活血红素，从而导致 sGC 降解。 NO-血红素信号对氧化应激的这种脆弱性导致了一种不依赖于 NO 的 sGC 激活剂 cinaciguat (BAY 58-2667) 的发现，它是临床试验中治疗急性失代偿性心力衰竭的候选药物。在这里，我们提供了揭示 BAY 58-2667 作用模式的晶体学和诱变数据。 BAY 58-2667 与来自发菜的血红素 NO 和氧结合域 (H-NOX) 结合的 2.3 埃分辨率结构与 sGC 同源，表明三叉 BAY 58-2667 分子已取代血红素并充当血红素模拟物。 BAY 58-2667 的羧酸酯基团产生类似于血红素丙酸酯基团的相互作用，而其疏水性苯环连接基以平面状方式在血红素腔内折叠。 BAY 58-2667 结合导致 α F 螺旋旋转远离血红素袋，因为该螺旋通常通过抑制性 His(105)-血红素共价键固定到位。该结构提供了有关 BAY 58-2667 如何结合并激活 sGC 以挽救心血管疾病中血红素-NO 功能障碍的见解。
Heme is a vital molecule for all life forms with heme being capable of assisting in catalysis, binding ligands, and undergoing redox changes. Heme-related dysfunction can lead to cardiovascular diseases with the oxidation of the heme of soluble guanylyl cyclase (sGC) critically implicated in some of these cardiovascular diseases. sGC, the main nitric oxide (NO) receptor, stimulates second messenger cGMP production, whereas reactive oxygen species are known to scavenge NO and oxidize/inactivate the heme leading to sGC degradation. This vulnerability of NO-heme signaling to oxidative stress led to the discovery of an NO-independent activator of sGC, cinaciguat (BAY 58-2667), which is a candidate drug in clinical trials to treat acute decompensated heart failure. Here, we present crystallographic and mutagenesis data that reveal the mode of action of BAY 58-2667. The 2.3-angstrom resolution structure of BAY 58-2667 bound to a heme NO and oxygen binding domain (H-NOX) from Nostoc homologous to that of sGC reveals that the trifurcated BAY 58-2667 molecule has displaced the heme and acts as a heme mimetic. Carboxylate groups of BAY 58-2667 make interactions similar to the heme-propionate groups, whereas its hydrophobic phenyl ring linker folds up within the heme cavity in a planar-like fashion. BAY 58-2667 binding causes a rotation of the alpha F helix away from the heme pocket, as this helix is normally held in place via the inhibitory His(105)-heme covalent bond. The structure provides insights into how BAY 58-2667 binds and activates sGC to rescue heme-NO dysfunction in cardiovascular diseases.