A Small Contribution to a Large System: The Leptin Receptor Complex
A Small Contribution to a Large System: The Leptin Receptor Complex
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对大系统的微小贡献：瘦素受体复合体
DOI：
10.1021/acs.jpcb.3c01090
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Haglund, Ellinor
中科院分区：
文献类型：
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作者：
Simien, Jennifer M.;Orellana, Grace E.;Phan, Hoa T.N.;Hu, Yao;Kurth, Emily A.;Ruf, Christine;Kricek, Franz;Wang, Qian;Smrcka, Alan V.;Haglund, Ellinor
肥胖是一种分类流行病，会增加糖尿病、炎症、心血管疾病和癌症等继发性疾病的风险。多效性激素瘦素被认为是肠道-脑轴控制营养状态和能量消耗的纽带。瘦素信号转导的研究为发现针对瘦素及其同源受体(LEP-R)的肥胖症及其相关疾病的治疗药物提供了广阔的前景。由于缺乏关于生物活性复合体的结构信息，人类瘦素受体复合体组装的分子基础仍然不清楚。在这项工作中，我们利用设计的拮抗剂蛋白结合AlphaFold预测来研究人瘦素中拟议的受体结合部位。我们的结果表明，结合位点I在活性信号复合体中具有比先前描述的更复杂的作用。我们假设，该区域的疏水斑块与第三个受体结合，形成一个更高阶的复合体，或者一个新的LEP-R结合部位，引起变构重排。
Obesity is a classified epidemic, increasing the risk of secondary diseases such as diabetes, inflammation, cardiovascular disease, and cancer. The pleiotropic hormone leptin is the proposed link for the gut-brain axis controlling nutritional status and energy expenditure. Research into leptin signaling provides great promise toward discovering therapeutics for obesity and its related diseases targeting leptin and its cognate leptin receptor (LEP-R). The molecular basis underlying the human leptin receptor complex assembly remains obscure, due to the lack of structural information regarding the biologically active complex. In this work, we investigate the proposed receptor binding sites in human leptin utilizing designed antagonist proteins combined with AlphaFold predictions. Our results show that binding site I has a more intricate role in the active signaling complex than previously described. We hypothesize that the hydrophobic patch in this region engages a third receptor forming a higher-order complex, or a new LEP-R binding site inducing allosteric rearrangement.