Dipartimento di Farmacia, Università di Napoli Federico II , 80131 Naples , Italy.
Istituto di Biostrutture e Bioimmagini, C.N.R. , 80134 Naples , Italy.
J Med Chem. 2018 Apr 12;61(7):2910-2923. doi: 10.1021/acs.jmedchem.7b01830. Epub 2018 Mar 19.
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.
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因子。评估配体在膜受体（如 GPCR）中与受体结合的构象对于设计更有效的类似物的合理药物设计具有重要意义。在这项工作中，我们应用了多种基于配体的核磁共振（NMR）方法来研究源自 C-X-C 基序趋化因子 12（CXCL12）的肽七聚体与 C-X-C 趋化因子受体 4（CXCR4）在人 T 白血病细胞（CCRF-CEM 细胞）膜上的相互作用。这项研究代表了首次在活细胞上直接对 GPCR 进行肽结合构象的结构研究。在 CXCL12/CXCR4 领域获得的结果虽然为研究 CXCR4 领域的人员提供了重要信息，但只是概念验证。所提出的 NMR 方法的一般应用是可能的，并且肯定有助于促进针对 GPCR 的新型治疗剂的开发。
