Structural Basis for Apelin Control of the Human Apelin Receptor
Structural Basis for Apelin Control of the Human Apelin Receptor
复制标题
Apelin 控制人 Apelin 受体的结构基础
DOI：
10.1016/j.str.2017.04.008
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发表时间：
2017-06-06
期刊：
影响因子：
5.7
通讯作者：
Xu, Fei
中科院分区：
文献类型：
--
作者：
Ma, Yingli;Yue, Yang;Xu, Fei
爱帕琳受体（Apelin receptor，APJR）是人类心血管功能的关键调节因子，并且被两种不同的内源性肽配体爱帕琳和Elabela激活，每种具有长度和氨基酸序列多样化的不同同种型。在这里，我们报告的2.6-A分辨率的晶体结构的人APJR在复杂的设计17个氨基酸的爱帕琳肽模拟肽激动剂。结构表明，该肽激动剂采用内酰胺限制的弯曲的两位点配体结合模式。结合突变分析和apelin-13与野生型APJR结合的分子动力学模拟，这种结构提供了对apelin识别和结合特异性的机制理解。这种结构与其他肽受体的比较表明，具有高度构象灵活性的内源性肽配体可以通过类似的两个位点结合机制结合和调节受体。
Apelin receptor (APJR) is a key regulator of human cardiovascular function and is activated by two different endogenous peptide ligands, apelin and Elabela, each with different isoforms diversified by length and amino acid sequence. Here we report the 2.6-A resolution crystal structure of human APJR in complex with a designed 17-amino-acid apelin mimetic peptide agonist. The structure reveals that the peptide agonist adopts a lactam constrained curved two-site ligand binding mode. Combined with mutation analysis and molecular dynamics simulations with apelin-13 binding to the wild-type APJR, this structure provides a mechanistic understanding of apelin recognition and binding specificity. Comparison of this structure with that of other peptide receptors suggests that endogenous peptide ligands with a high degree of conformational flexibility may bind and modulate the receptors via a similar two site binding mechanism.