Molecular Signature for Receptor Engagement in the Metabolic Peptide Hormone Amylin
Molecular Signature for Receptor Engagement in the Metabolic Peptide Hormone Amylin
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DOI：
10.1021/acsptsci.8b00002
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发表时间：
2018-09-14
影响因子：
--
通讯作者：
Hay, Debbie L.
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文献类型：
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作者：
Bower, Rebekah L.;Yule, Lauren;Hay, Debbie L.
胰肽激素amylin在食欲控制中起关键作用，并与其他关键代谢激素如胰高血糖素样肽1 （GLP-1）协同作用。有机会开发有效和长效的胰淀素类似物或它们与GLP-1模拟物之间的杂交物来治疗肥胖。为了实现这一目标，需要对37个氨基酸的胰肽如何与其复杂的受体系统进行研究。我们合成了一个广泛的肽库来分析人类胰淀素序列，确定其二硫环、修饰的c端和受体“捕获”和“激活”区域在受体信号传导中的作用。除了探索相关受体之间的选择性决定因素外，我们还分析了多种受体亚型上不同配体的四种信号通路。肽亚区在受体结合和激活中的不同作用被确定，导致肽具有比天然序列更大的活性。增强的肽活性保留在脑干中，这是胰淀素的主要生物学靶点。利用分子动力学、元动力学和监督分子动力学模拟支持的全长活性受体模型对我们的数据进行解释，指导了GLP-1和amylin受体的强效双重激动剂的合成。这些数据为肽酰胺化的功能、变构如何驱动肽受体相互作用提供了新的见解，并为开发用于治疗糖尿病和肥胖症的新型胰淀素激动剂提供了宝贵的资源。
The pancreatic peptide hormone, amylin, plays a critical role in the control of appetite, and synergizes with other key metabolic hormones such as glucagon-like peptide 1 (GLP-1). There is opportunity to develop potent and long-acting analogues of amylin or hybrids between these and GLP-1 mimetics for treating obesity. To achieve this, interrogation of how the 37 amino acid amylin peptide engages with its complex receptor system is required. We synthesized an extensive library of peptides to profile the human amylin sequence, determining the role of its disulfide loop, amidated C-terminus and receptor "capture" and "activation" regions in receptor signaling. We profiled four signaling pathways with different ligands at multiple receptor subtypes, in addition to exploring selectivity determinants between related receptors. Distinct roles for peptide subregions in receptor binding and activation were identified, resulting in peptides with greater activity than the native sequence. Enhanced peptide activity was preserved in the brainstem, the major biological target for amylin. Interpretation of our data using full-length active receptor models supported by molecular dynamics, metadynamics, and supervised molecular dynamics simulations guided the synthesis of a potent dual agonist of GLP-1 and amylin receptors. The data offer new insights into the function of peptide amidation, how allostery drives peptide-receptor interactions, and provide a valuable resource for the development of novel amylin agonists for treating diabetes and obesity.