一氧化氮（NO）调节动物生理的大部分领域，包括伤口愈合、血管舒张、记忆形成、气味检测、性功能和对感染性疾病的反应。主要的NO受体是可溶性鸟苷酸环化酶（sGC），这是一种150 kDa的二聚蛋白，通过亚铁血红素检测NO，导致构象发生巨大变化并增加从GTP生成cGMP的产量。在人类中，sGC功能丧失有助于多种疾病状态的发生，包括心血管疾病和癌症，并且成为一类新药物sGC刺激剂的靶点，目前已经在临床应用中。sGC通过四个古老结构域的融合而进化而来，这四个结构域是血红素一氧化氮/氧（H-NOX）结构域、Per-ARNT-Sim（PAS）结构域、螺旋卷曲和环化酶结构域，催化作用发生在两个环化酶结构域的接口处。在动物中，占主导地位的二聚体是α1β1异二聚体，其中α1亚单位通过β1亚单位的基因复制形成。PAS结构域提供了一个广泛的二聚体界面，在sGC激活过程中保持不变，作为核心锚点。在PAS-PAS二聚体界面形成一个大裂缝，紧密结合螺旋卷末端的N-端，使该区域保持完整不变，而螺旋卷的其余部分重新排列位置。该界面埋藏了约3000 Å2的单体表面，并包含高度保守的非极性和氢键残基。在这里，我们讨论了sGC的进化历史，描述了PAS结构域在sGC功能中的作用，并探索了影响sGC功能的调控因素。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

Nitric oxide (NO) regulates large swaths of animal physiology including wound healing, vasodilation, memory formation, odor detection, sexual function, and response to infectious disease. The primary NO receptor is soluble guanyly/guanylate cyclase (sGC), a dimeric protein of ∼150 kDa that detects NO through a ferrous heme, leading to a large change in conformation and enhanced production of cGMP from GTP. In humans, loss of sGC function contributes to multiple disease states, including cardiovascular disease and cancer, and is the target of a new class of drugs, sGC stimulators, now in clinical use. sGC evolved through the fusion of four ancient domains, a heme nitric oxide / oxygen (H-NOX) domain, a Per-ARNT-Sim (PAS) domain, a coiled coil, and a cyclase domain, with catalysis occurring at the interface of the two cyclase domains. In animals, the predominant dimer is the α1β1 heterodimer, with the α1 subunit formed through gene duplication of the β1 subunit. The PAS domain provides an extensive dimer interface that remains unchanged during sGC activation, acting as a core anchor. A large cleft formed at the PAS-PAS dimer interface tightly binds the N-terminal end of the coiled coil, keeping this region intact and unchanged while the rest of the coiled coil repacks, and the other domains reposition. This interface buries ∼3000 Å2 of monomer surface and includes highly conserved apolar and hydrogen bonding residues. Herein, we discuss the evolutionary history of sGC, describe the role of PAS domains in sGC function, and explore the regulatory factors affecting sGC function.Copyright © 2023 Elsevier Ltd. All rights reserved.