Department of Biosciences, COMSATS University, Islamabad 45550, Pakistan.
Department of Biology, University of Crete, 70013 Heraklion, Greece.
Int J Mol Sci. 2019 Feb 6;20(3):698. doi: 10.3390/ijms20030698.
Soluble guanylate cyclase (sGC) regulates numerous physiological processes. The β subunit Heme Nitric Oxide/Oxygen (HNOX) domain makes this protein sensitive to small gaseous ligands. The structural basis of the activation mechanism of sGC under the influence of ligands (NO, O₂, CO) is poorly understood. We examine the effect of different ligands on the human sGC HNOX domain. HNOX systems with gaseous ligands were generated and explored using Molecular Dynamics (MD). The distance between heme Fe and histidine in the NO-ligated HNOX (NO-HNOX) system is larger compared to the O₂, CO systems. NO-HNOX rapidly adopts the conformation of the five-group metal coordination system. Loops α, β, γ and helix-f exhibit increased mobility and different hydrogen bond networks in NO-HNOX compared to the other systems. The removal of His from the Fe coordination sphere in NO-HNOX is assisted by interaction of the imidazole ring with the surrounding residues which in turn leads to the release of signaling helix-f and activation of the sGC enzyme. Insights into the conformational dynamics of a human sGC HNOX domain, especially for regions which are functionally critical for signal transduction, are valuable in the understanding of cardiovascular diseases.
可溶性鸟苷酸环化酶（sGC）调节着许多生理过程。β亚基血红素一氧化氮/氧（HNOX）结构域使该蛋白对小气体配体敏感。在配体（NO、O₂、CO）的影响下，sGC 的激活机制的结构基础理解甚少。我们研究了不同配体对人 sGC HNOX 结构域的影响。使用分子动力学（MD）生成并探索了具有气态配体的 HNOX 系统。与 O₂、CO 系统相比，NO 配位的 HNOX（NO-HNOX）系统中血红素 Fe 和组氨酸之间的距离更大。NO-HNOX 迅速采用五配位金属配位系统的构象。与其他系统相比，NO-HNOX 中的α、β、γ环和螺旋-f 表现出更高的流动性和不同的氢键网络。NO-HNOX 中 His 从 Fe 配位球中的去除受到咪唑环与周围残基相互作用的辅助，这反过来又导致信号传导螺旋-f 的释放和 sGC 酶的激活。对人 sGC HNOX 结构域构象动力学的深入了解，特别是对功能上对信号转导至关重要的区域的了解，对于理解心血管疾病非常有价值。
