Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs.

中文翻译：

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基于配体的4型CXC趋化因子受体（CXCR4）的NMR研究–配体在活癌细胞上的相互作用

肽结合G蛋白偶联受体（GPCR）是许多病理和生理途径中的关键效应子。膜受体（例如GPCR）中肽配体的受体结合构象的评估对于更有效的类似物的合理药物设计具有重大影响。在这项工作中，我们应用了多种基于配体的核磁共振（NMR）方法来研究人膜上源自CXC Motif趋化因子12（CXCL12）和CXC趋化因子受体4（CXCR4）的肽七聚体的相互作用。 T白血病细胞（CCRF-CEM细胞）。这项研究代表了第一个结构研究，报告了直接在活细胞上肽与GPCR的受体结合构象。在CXCL12 / CXCR4领域获得的结果是概念证明，尽管出现了有关CXCR4领域研究人员的重要信息。提出的NMR方法学的普遍应用是可能的，并且肯定可以帮助促进靶向GPCR的新治疗剂的开发。