The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.
The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.
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DOI：
10.1016/j.cell.2016.05.023
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发表时间：
2016-06-16
期刊：
影响因子：
64.5
通讯作者：
Sexton PM
中科院分区：
文献类型：
--
作者：
Wootten D;Reynolds CA;Smith KJ;Mobarec JC;Koole C;Savage EE;Pabreja K;Simms J;Sridhar R;Furness SGB;Liu M;Thompson PE;Miller LJ;Christopoulos A;Sexton PM
配体导向的信号偏差为塑造分子事件提供了机会，并有望提供更好，更安全的治疗方法。关键的信号偏差的开发是一个耦合配体结合细胞内信号的分子事件的理解。B G类蛋白偶联受体的活化是由肽N末端与受体核心的相互作用驱动的。为了理解这是如何驱动信号传导的，我们使用了先进的分析方法，这些方法能够将对通路特异性信号传导的影响与那些改变激动剂亲和力的影响分开，并将受体修饰的功能后果映射到受体-配体复合物的三维模型上。这产生了对受体激活的起始和偏向激动的机制基础的分子见解。我们的数据显示，肽激动剂可以接合受体细胞外表面的不同元件，以实现效应器偶联和偏置信号传导，为合理设计偏置激动剂提供了基础。突变对映射到3D模型上的偏向性配体的亲和力和功效的影响偏向性激动剂与GLP-1 R细胞外表面形成独特的相互作用细胞外表面独特元件的接合促进偏向性激动剂对B类GPCR激活/偏向性激动剂的见解有助于合理的药物设计了解不同的配体如何接合并激活GLP-1受体下游的信号通路，一个关键的II型糖尿病的目标，建议的战略，塑造信号的结果，有利于生理上有益的影响。
Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists. Effect of mutation on affinity and efficacy of biased ligands mapped onto 3D models Biased agonists form distinct interactions with the GLP-1R extracellular surface Engagement of unique elements of the extracellular surface promotes biased agonism Insights into class B GPCR activation/biased agonism can aid rational drug design Understanding how different ligands engage and activate signaling pathways downstream of the GLP-1 receptor, a key type II diabetes target, suggests strategies for shaping signaling outcomes to favor physiologically beneficial effects.