Nature突破:靠吃药就能不饿?科学家们向前迈进重要一步
2018/05/01
最新发表在Nature杂志上的一项研究中,一个国际科学家小组在对抗肥胖研究方向上取得突破进展,首次描述了一种复杂的、被激活后能够抑制饥饿的受体的关键结构信息,为治疗肥胖、糖尿病等疾病的药物研发提供了重要的依据。


图片来源:Nature(doi:10.1038/s41586-018-0046-x)

中国科学院上海药物研究所吴蓓丽研究员、德国莱比锡大学Annette G. Beck-Sickinger教授以及德国雷根斯堡大学Max Keller博士是这篇题为“Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor”的论文的共同通讯作者。

作者们表示,制药公司长期以来一直在尝试开发能够抑制饥饿的小分子药物,然而,先前一直没有人确切地知道相关受体也就是药物的靶点)是什么样的,这就使得开发调节这些受体的药物变得非常困难。

神经肽Y是最重要的神经肽类物质之一,在细胞内通过与其受体结合,发挥调节食物摄取、能量平衡等重要功能。在这项研究中,科学家们将目光锁定在了“神经肽Y受体”上(在人体内,神经肽Y受体包括Y1R、Y2R、Y4R和Y5R四种亚型,神经肽Y主要通过激活Y1R刺激食欲),并确定了神经肽Y受体Y1R的首个晶体结构,破译了数以千计组成该受体的碳、氧、氮和其他原子以及它们是如何相互结合的。


Jens Meiler's team determined the first crystal structure for a neuropeptide Y receptor, deciphering the thousands of carbon, oxygen, nitrogen and other atoms involved with it and how they bind to one another. Credit: Brian Bender/Vanderbilt University

参与该研究的Jens Meiler教授说:“这是药物发现过程中一个非常重要的里程牌。这篇论文的最大贡献是弄清了组成Y1R的所有原子的空间位置以及各原子之间的结合方式。在不清楚Y1R结构前设计靶向它的药物,就好比在不知道钥匙孔形状的情况下来设计钥匙。而现在,我们已经清楚的知道,该受体的结构中存在一些能够让小分子药物结合的‘小口袋’。


图片来源:16sucai

先前已有研究表明,当Y1R这一受体的功能被阻断后,小鼠会变得肥胖。接下来,科学家们要做的就是靶点验证:证明该受体确实能够控制饥饿。

“正常情况下,一旦你吃了东西,机体就会产生神经肽Y来激活Y1R,然后,你就会不再感到饥饿,从而停止进食。我们的想法是,通过小分子药物直接上调Y1R的活性(也就是不靠吃东西,而用药物激活Y1R),从而产生不饿的感觉,达到少吃的目的。”Meiler教授解释道。

责编:风铃

参考资料:

Characterizing 'keyhole' is first step to fighting obesity at cellular level

抗肥胖药物靶点研究的新突破——神经肽Y受体Y1R的三维结构揭示药物分子作用机制

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  • Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor

    Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology1,2. The NPY–Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y1, Y2, Y4 and Y5 receptors, with different affinity and selectivity3. NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y1 receptor (Y1R)4. A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity4, tumour1 and bone loss5. However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability6. Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.

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