Structure of the dimerized hormone-binding domain of a guanylyl-cyclase-coupled receptor
Structure of the dimerized hormone-binding domain of a guanylyl-cyclase-coupled receptor
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DOI：
10.1038/35017602
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发表时间：
2000-07-06
期刊：
影响因子：
64.8
通讯作者：
Yee, VC
中科院分区：
文献类型：
--
作者：
van den Akker, F;Zhang, XL;Yee, VC
心房利钠肽（ANP）激素是由心脏分泌的，以响应血压的升高。ANP在肾脏、肾上腺和血管系统中表现出几种有效的抗高血压作用。这些作用是由激素在细胞外与ANP受体结合引起的（1），从而激活其细胞内鸟苷酸环化酶结构域，产生环GMP（2）。在这里，我们提出了在2.0埃分辨率的ANP受体的糖基化二聚体的结合结构域的晶体结构。该单体包含两个相互连接的亚结构域，每个亚结构域包含一个侧接α-螺旋的中心β-折叠，并表现出I型周质结合蛋白折叠。二聚化由两两排列的四个平行螺旋的并置介导，这使得两个突出的羧基末端相对接近。从亲和标记和诱变研究，ANP结合位点映射到二聚体裂缝的一侧，并延伸到二聚体界面附近。一个保守的氯离子结合位点位于膜远端结构域，我们发现激素结合是氯离子依赖性的。这些研究提示了激素激活和ANP受体变构的机制。
The atrial natriuretic peptide (ANP) hormone is secreted by the heart in response to an increase in blood pressure. ANP exhibits several potent anti-hypertensive actions in the kidney, adrenal gland and vascular system. These actions are induced by hormone binding extracellularly to the ANPreceptor(1), thereby activating its intracellular guanylyl cyclase domain for the production of cyclic GMP(2). Here we present the crystal structure of the glycosylated dimerized hormone-binding domain of the ANP receptor at 2.0-Angstrom resolution. The monomer comprises two interconnected subdomains, each encompassing a central beta-sheet flanked by alpha-helices, and exhibits the type I periplasmic binding protein fold. Dimerization is mediated by the juxtaposition of four parallel helices, arranged two by two, which brings the two protruding carboxy termini into close relative proximity. From affinity labelling and mutagenesis studies, the ANP-binding site maps to the side of the dimer crevice and extends to near the dimer interface. A conserved chloride-binding site is located in the membrane distal domain, and we found that hormone binding is chloride dependent. These studies suggest mechanisms for hormone activation and the allostery of the ANP receptor.