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Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2017-12-11 , DOI: 10.1038/nchembio.2527
John D McCorvy , Kyle V Butler , Brendan Kelly , Katie Rechsteiner , Joel Karpiak , Robin M Betz , Bethany L Kormos , Brian K Shoichet , Ron O Dror , Jian Jin , Bryan L Roth

Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid–ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy may facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands.



中文翻译:

胺能性GPCR的β-arrestin偏置配体的结构启发设计

针对G蛋白偶联受体(GPCR)的有偏配体的开发是当前药物发现的一种有前途的方法。尽管即使有大量的GPCR晶体结构,偏向激动剂的基于结构的药物设计仍然具有挑战性,但我们提出了一种将GPCR结构数据转化为β-arrestin偏向于胺能性GPCR的配体的方法。我们确定了分别负责Gi / o和β-arrestin信号传导的跨膜螺旋5(TM5)和细胞外环2(EL2)的特定氨基酸-配体接触,并将这些残基作为靶点来开发有偏性的配体。对于这些配体,我们发现在其他胺能GPCR上保留了偏倚,而其他胺能GPCR在TM5和EL2上保留了相似的残基。我们的方法提供了一个模板,可通过修改预测的配体相互作用(阻止TM5相互作用并促进EL2相互作用)来生成抑制蛋白的配体。此策略可能有助于其他GPCR处抑制蛋白偏向配体的结构指导设计,包括多药理学偏向配体。

更新日期:2017-12-11
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