一氧化氮(NO)调节大片动物生理学,包括伤口愈合,血管舒张,记忆形成,气味检测,性功能,以及对传染病的反应。主要的NO受体是可溶性鸟苷酸环化酶(sGC),150kDa的二聚体蛋白,通过亚铁血红素检测NO,导致构象发生巨大变化,并提高了GTP的cGMP产量。在人类中,sGC功能的丧失导致多种疾病状态,包括心血管疾病和癌症,是一类新型药物的目标,sGC刺激器,现在在临床使用。sGC是通过四个古老领域的融合而进化而来的,血红素一氧化氮/氧(H-NOX)域,a每ARNT-Sim(PAS)域,一个盘绕的线圈,和一个环化酶结构域,催化发生在两个环化酶结构域的界面。在动物中,主要的二聚体是α1β1异二聚体,通过β1亚基的基因复制形成α1亚基。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,充当核心锚。在PAS-PAS二聚体界面处形成的大裂口与卷曲螺旋的N末端紧密结合,保持这个区域的完整和不变,而其余的卷曲线圈重新包装,和其他域重新定位。该界面掩埋了单体表面的〜3000µ2,并包括高度保守的非极性和氢键残基。在这里,我们讨论了sGC的进化史,描述PAS域在sGC功能中的作用,探讨影响sGC功能的调控因素。
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.