Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
Institute of Biophysical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
Nat Chem Biol. 2018 Mar;14(3):284-290. doi: 10.1038/nchembio.2551. Epub 2018 Jan 15.
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors. Analysis of the peptide-receptor interfaces reveals that the charged N-terminal residues of the peptides are mainly selected through electrostatic interactions, whereas the C-terminal segments are recognized via both conformations and interactions. The detailed molecular picture obtained by this approach opens a new gateway for exploring the complex conformational and chemical space of peptides and peptide analogs for designing GPCR subtype-selective biochemical tools and drugs.
G 蛋白偶联受体（GPCRs）是高等真核生物中最重要的信号转导分子。尽管已经取得了相当大的进展，但亚型特异性配体选择性的分子基础，特别是对于肽受体，仍然未知。在这里，通过将 DNP 增强的固态 NMR 光谱学与先进的分子建模和对接相结合，解决了人类缓激肽受体对其肽激动剂的亚型选择性的机制。结合肽的保守中间片段显示出不同的构象，导致其 N 和 C 末端呈现出不同的受体取向。对肽-受体界面的分析表明，肽的带电荷的 N 末端残基主要通过静电相互作用被选择，而 C 末端片段则通过构象和相互作用被识别。通过这种方法获得的详细分子图像为探索肽和肽类似物的复杂构象和化学空间打开了新的途径，可用于设计 GPCR 亚型选择性生化工具和药物。
