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Solution structures of the Shewanella woodyi H‐NOX protein in the presence and absence of soluble guanylyl cyclase stimulator IWP‐051
Protein Science ( IF 4.5 ) Pub Date : 2020-11-25 , DOI: 10.1002/pro.4005
Cheng-Yu Chen 1 , Woonghee Lee 2, 3 , Paul A Renhowe 4 , Joon Jung 4 , William R Montfort 1
Affiliation  

Heme‐nitric oxide/oxygen binding (H‐NOX) domains bind gaseous ligands for signal transduction in organisms spanning prokaryotic and eukaryotic kingdoms. In the bioluminescent marine bacterium Shewanella woodyi (Sw), H‐NOX proteins regulate quorum sensing and biofilm formation. In higher animals, soluble guanylyl cyclase (sGC) binds nitric oxide with an H‐NOX domain to induce cyclase activity and regulate vascular tone, wound healing and memory formation. sGC also binds stimulator compounds targeting cardiovascular disease. The molecular details of stimulator binding to sGC remain obscure but involve a binding pocket near an interface between H‐NOX and coiled‐coil domains. Here, we report the full NMR structure for CO‐ligated Sw H‐NOX in the presence and absence of stimulator compound IWP‐051, and its backbone dynamics. Nonplanar heme geometry was retained using a semi‐empirical quantum potential energy approach. Although IWP‐051 binding is weak, a single binding conformation was found at the interface of the two H‐NOX subdomains, near but not overlapping with sites identified in sGC. Binding leads to rotation of the subdomains and closure of the binding pocket. Backbone dynamics are similar across both domains except for two helix‐connecting loops, which display increased dynamics that are further enhanced by compound binding. Structure‐based sequence analyses indicate high sequence diversity in the binding pocket, but the pocket itself appears conserved among H‐NOX proteins. The largest dynamical loop lies at the interface between Sw H‐NOX and its binding partner as well as in the interface with the coiled coil in sGC, suggesting a critical role for the loop in signal transduction.

中文翻译:

Shewanella woodyi H-NOX 蛋白在可溶性鸟苷酸环化酶刺激物 IWP-051 存在和不存在下的溶液结构

血红素-一氧化氮/氧结合 (H-NOX) 结构域结合气态配体,用于跨越原核和真核生物界的生物体中的信号转导。在生物发光的海洋细菌Shewanella woodyi ( Sw ) 中,H-NOX 蛋白调节群体感应和生物膜形成。在高等动物中,可溶性鸟苷酸环化酶 (sGC) 将一氧化氮与 H-NOX 结构域结合以诱导环化酶活性并调节血管张力、伤口愈合和记忆形成。sGC 还结合针对心血管疾病的刺激化合物。刺激物与 sGC 结合的分子细节仍然不清楚,但在 H-NOX 和卷曲螺旋结构域之间的界面附近有一个结合袋。在这里,我们报告了 CO 连接的Sw的完整 NMR 结构H-NOX 在刺激剂化合物 IWP-051 存在和不存在的情况下,及其骨架动力学。使用半经验量子势能方法保留了非平面血红素几何形状。尽管 IWP-051 结合较弱,但在两个 H-NOX 亚结构域的界面处发现了单一的结合构象,靠近但不与 sGC 中识别的位点重叠。结合导致子结构域的旋转和结合袋的闭合。除了两个螺旋连接环外,两个域的骨干动力学相似,它们显示出增加的动力学,复合结合进一步增强了这些动力学。基于结构的序列分析表明结合口袋中的高序列多样性,但口袋本身在 H-NOX 蛋白中似乎是保守的。最大的动态回路位于Sw之间的界面处H-NOX 及其结合伙伴以及与 sGC 中盘绕线圈的界面,表明环在信号转导中的关键作用。
更新日期:2021-01-05
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