Department of Life and Environmental Sciences - New York-Marche Structural Biology Centre (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, 60131, Ancona, Italy.
Neuronal Death and Neuroprotection Unit, Department of Neuroscience, Mario Negri Institute for Pharmacological Research-IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Nat Commun. 2023 Oct 13;14(1):6439. doi: 10.1038/s41467-023-42082-z.
G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4 by means of an advanced free-energy technique named coarse-grained metadynamics. Our results reproduce binding events between the GPCRs occurring in the minute timescale, revealing a symmetric and an asymmetric dimeric structure for each of the three investigated systems, CCR5/CCR5, CXCR4/CXCR4, and CCR5/CXCR4. The transmembrane helices TM4-TM5 and TM6-TM7 are the preferred binding interfaces for CCR5 and CXCR4, respectively. The identified dimeric states differ in the access to the binding sites of the ligand and G protein, indicating that dimerization may represent a fine allosteric mechanism to regulate receptor activity. Our study offers structural basis for the design of ligands able to modulate the formation of CCR5 and CXCR4 dimers and in turn their activity, with therapeutic potential against HIV, cancer, and immune-inflammatory diseases.
G 蛋白偶联受体（GPCRs）是负责细胞外到细胞内信号转导的重要药物靶点。GPCR 可以形成功能二聚体，但迄今为止对其了解甚少。在这里，我们通过一种名为粗粒元分子动力学的先进自由能技术，展示了趋化因子受体 CCR5 和 CXCR4 的二聚化机制。我们的结果再现了在微小时间尺度上发生的 GPCR 之间的结合事件，揭示了三个研究系统（CCR5/CCR5、CXCR4/CXCR4 和 CCR5/CXCR4）中每一种的对称和不对称二聚体结构。TM4-TM5 和 TM6-TM7 跨膜螺旋是 CCR5 和 CXCR4 的首选结合界面。所鉴定的二聚体状态在配体和 G 蛋白结合位点的可及性上存在差异，表明二聚化可能代表一种精细的变构机制，以调节受体活性。我们的研究为设计能够调节 CCR5 和 CXCR4 二聚体形成及其活性的配体提供了结构基础，从而具有针对 HIV、癌症和免疫炎症性疾病的治疗潜力。
